Azaindoles useful as inhibitors of JAK and other protein kinases

ABSTRACT

The present invention relates to inhibitors of protein kinases. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/557,503, filed Mar. 30, 2004 and U.S. Provisional Application No.60/625,599, filed Nov. 5, 2004.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to inhibitors of protein kinases. Theinvention also provides pharmaceutical compositions comprising thecompounds of the invention and methods of using the compositions in thetreatment of various disorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. (See, Hardie, G. and Hanks, S.The Protein Kinase Facts Book, I and II, Academic Press, San Diego,Calif.: 1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these kinase families(See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596;Knighton et al., Science 1991, 253, 407-414; Hiles et al., Cell 1992,70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al.,EMBO J. 1994, 13, 2352-2361).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1)and tumor necrosis factor α (TNF-α)), and growth factors (e.g.,granulocyte macrophage-colony-stimulating factor (GM-CSF), andfibroblast growth factor (FGF)). An extracellular stimulus may affectone or more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, autoimmune diseases, inflammatorydiseases, bone diseases, metabolic diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease, and hormone-related diseases.Accordingly, there has been a substantial effort in medicinal chemistryto find protein kinase inhibitors that are effective as therapeuticagents.

The Janus kinases (JAK) are a family of tyrosine kinases consisting ofJAK1, JAK2, JAK3 and TYK2. The JAKs play a critical role in cytokinesignaling. The down-stream substrates of the JAK family of kinasesinclude the signal transducer and activator of transcription (STAT)proteins. JAK/STAT signaling has been implicated in the mediation ofmany abnormal immune responses such as allergies, asthma, autoimmunediseases such as transplant rejection, rheumatoid arthritis, amyotrophiclateral sclerosis and multiple sclerosis as well as in solid andhematologic malignancies such as leukemias and lymphomas. Thepharmaceutical intervention in the JAK/STAT pathway has been reviewed[Frank Mol. Med. 5, 432-456 (1999) & Seidel, et al, Oncogene 19,2645-2656 (2000)].

JAK1, JAK2, and TYK2 are ubiquitously expressed, while JAK3 ispredominantly expressed in hematopoietic cells. JAK3 binds exclusivelyto the common cytokine receptor gamma chain (γ_(c)) and is activated byIL-2, IL-4, IL-7, IL-9, and IL-15. The proliferation and survival ofmurine mast cells induced by IL-4 and IL-9 have, in fact, been shown tobe dependent on JAK3- and γ_(c)-signaling [Suzuki et al, Blood 96,2172-2180 (2000)].

Cross-linking of the high-affinity immunoglobulin (Ig) E receptors ofsensitized mast cells leads to a release of proinflammatory mediators,including a number of vasoactive cytokines resulting in acute allergic,or immediate (type I) hypersensitivity reactions [Gordon et al, Nature346, 274-276 (1990) & Galli, N. Engl. J. Med., 328, 257-265 (1993)]. Acrucial role for JAK3 in IgE receptor-mediated mast cell responses invitro and in vivo has been established [Malaviya, et al, Biochem.Biophys. Res. Commun. 257, 807-813 (1999)]. In addition, the preventionof type I hypersensitivity reactions, including anaphylaxis, mediated bymast cell-activation through inhibition of JAK3 has also been reported[Malaviya et al, J. Biol. Chem. 274, 27028-27038 (1999)]. Targeting mastcells with JAK3 inhibitors modulated mast cell degranulation in vitroand prevented IgE receptor/antigen-mediated anaphylactic reactions invivo.

A recent study described the successful targeting of JAK3 for immunesuppression and allograft acceptance. The study demonstrated adose-dependent survival of Buffalo heart allograft in Wistar Furthrecipients upon administration of inhibitors of JAK3 indicating thepossibility of regulating unwanted immune responses in graft versus hostdisease [Kirken, Transpl. Proc. 33, 3268-3270 (2001)].

IL-4-mediated STAT-phosphorylation has been implicated as the mechanisminvolved in early and late stages of rheumatoid arthritis (RA).Up-regulation of proinflammatory cytokines in RA synovium and synovialfluid is a characteristic of the disease. It has been demostrated thatIL-4-mediated activation of IL-4/STAT pathway is mediated through theJanus Kinases (JAK 1 & 3) and that IL-4-associated JAK kinases areexpressed in the RA synovium [Muller-Ladner, et al, J. Immunol. 164,3894-3901 (2000)].

Familial amyotrophic lateral sclerosis (FALS) is a fatalneurodegenerative disorder affecting about 10% of ALS patients. Thesurvival rates of FALS mice were increased upon treatment with a JAK3specific inhibitor. This suggested that JAK3 plays a role in FALS[Trieu, et al, Biochem. Biophys. Res. Commun. 267, 22-25 (2000)].

Signal transducer and activator of transcription (STAT) proteins areactivated by, among others, the JAK family kinases. Results form arecent study suggested the possibility of intervention in the JAK/STATsignaling pathway by targeting JAK family kinases with specificinhibitors for the treatment of leukemia [Sudbeck, et al, Clin. CancerRes. 5, 1569-1582 (1999)]. JAK3 specific compounds were shown to inhibitthe clonogenic growth of JAK3-expressing cell lines DAUDI, RAMOS, LC1;19, NALM-6, MOLT-3 and HL-60.

In animal models, TEL/JAK2 fusion proteins have inducedmyeloproliferative disorders and in hematopoietic cell lines,introduction of TEL/JAK2 resulted in activation of STAT1, STAT3, STAT5,and cytokine-independent growth [Schwaller, et al, EMBO J. 17, 5321-5333(1998)].

Inhibition of JAK 3 and TYK 2 abrogated tyrosine phosphorylation ofSTAT3, and inhibited cell growth of mycosis fungoides, a form ofcutaneous T cell lymphoma. These results implicated JAK family kinasesin the constitutively activated JAK/STAT pathway that is present inmycosis fungoides [Nielsen, et al, Proc. Nat. Acad. Sci. U.S.A. 94,6764-6769 (1997)]. Similarly, STAT3, STAT5, JAK1 and JAK2 weredemonstrated to be constitutively activated in mouse T cell lymphomacharacterized initially by LCK over-expression, thus further implicatingthe JAK/STAT pathway in abnormal cell growth [Yu, et al, J. Immunol.159, 5206-5210 (1997)]. In addition, IL-6-mediated STAT3 activation wasblocked by an inhibitor of JAK, leading to sensitization of myelomacells to apoptosis [Catlett-Falcone, et al, Immunity 10, 105-115(1999)].

One kinase family of interest is Rho-associated coiled-coil formingprotein serine/threonine kinase (ROCK), which is believed to be aneffector of Ras-related small GTPase Rho. The ROCK family includesp160ROCK (ROCK-1) (Ishizaki et al., EMBO J. 1996, 15, 1885-1893) andROKα/Rho-kinase/ROCK-II (Leung et al., J. Biol. Chem. 1995, 270,29051-29054; Matsui et al., EMBO J. 1996, 15, 2208-2216; Nakagawa etal., FEBS Lett. 1996, 392, 189-193), protein kinase PKN (Amano et al.,Science 1996, 271, 648-650; Watanabe et al., Science 1996, 271,645-648), and citron and citron kinase (Madaule et al. Nature, 1998,394, 491-494; Madaule et al., FEBS Lett. 1995, 377, 243-248). The ROCKfamily of kinases have been shown to be involved in a variety offunctions including Rho-induced formation of actin stress fibers andfocal adhesions (Leung et al., Mol. Cell Biol. 1996, 16, 5313-5327;Amano et al., Science, 1997, 275, 1308-1311; Ishizaki et al., FEBS Lett.1997, 404, 118-124) and in downregulation of myosin phosphatase (Kimuraet al., Science, 1996, 273, 245-248), platelet activation (Klages etal., J. Cell. Biol., 1999, 144, 745-754), aortic smooth musclecontraction by various stimuli (Fu et al., FEBS Lett., 1998, 440,183-187), thrombin-induced responses of aortic smooth muscle cells(Seasholtz et al., Cir. Res., 1999, 84, 1186-1193), hypertrophy ofcardiomyocytes (Kuwahara et al., FEBS Lett., 1999, 452, 314-318),bronchial smooth muscle contraction (Yoshii et al., Am. J. Respir. CellMol. Biol., 1999, 20, 1190-1200), smooth muscle contraction andcytoskeletal reorganization of non-muscle cells (Fukata et al., Trendsin Pharm. Sci 2001, 22, 32-39), activation of volume-regulated anionchannels (Nilius et al., J. Physiol., 1999, 516, 67-74), neuriteretraction (Hirose et al., J. Cell. Biol., 1998, 141, 1625-1636),neutrophil chemotaxis (Niggli, FEBS Lett., 1999, 445, 69-72), woundhealing (Nobes and Hall, J. Cell. Biol., 1999, 144, 1235-1244), tumorinvasion (Itoh et al., Nat. Med., 1999, 5, 221-225) and celltransformation (Sahai et al., Curr. Biol., 1999, 9, 136-145).

More specifically, ROCK has been implicated in various diseases anddisorders including hypertension (Satoh et al., J. Clin. Invest. 1994,94, 1397-1403; Mukai et al., FASEB J. 2001, 15, 1062-1064; Uehata etal., Nature 1997, 389, 990-994; Masumoto et al., Hypertension, 2001, 38,1307-1310), cerebral vasospasm (Sato et al., Circ. Res. 2000, 87,195-200; Miyagi et al., J. Neurosurg. 2000, 93, 471-476; Tachibana etal., Acta Neurochir (Wien) 1999, 141, 13-19), coronary vasospasm(Shimokawa et al., Jpn. Cir. J. 2000, 64, 1-12; Kandabashi et al.,Circulation 2000, 101, 1319-1323; Katsumata et al., Circulation 1997,96, 4357-4363; Shimokawa et al., Cardiovasc. Res. 2001, 51, 169-177;Utsunomiya et al., J. Pharmacol. 2001, 134, 1724-1730; Masumoto et al.,Circulation 2002, 105, 1545-1547), bronchial asthma (Chiba et al., Comp.Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol. 1995, 11, 351-357;Chiba et al., Br. J. Pharmacol. 1999, 127, 597-600; Chiba et al., Br. J.Pharmacol. 2001, 133, 886-890; Iizuka et al., Eur. J. Pharmacol. 2000,406, 273-279), preterm labor (Niro et al., Biochem. Biophys. Res.Commun. 1997, 230, 356-359; Tahara et al., Endocrinology 2002, 143,920-929; Kupittayanant et al., Pflugers Arch. 2001, 443, 112-114),erectile dysfunction (Chitaley et al., Nat. Med. 2001, 7, 119-122; Millset al., J. Appl. Physiol. 2001, 91, 1269-1273), glaucoma (Honjo et al.,Arch. Ophthalmol. 2001, 1171-1178; Rao et al., Invest. Ophthalmol. Vis.Sci. 2001, 42, 1029-1037), vascular smooth muscle cell proliferation(Shimokawa et al., Cardiovasc. Res. 2001, 51, 169-177; Morishige et al.,Arterioscler. Thromb. Vasc. Biol. 2001, 21, 548-554; Eto et al., Am. J.Physiol. Heart Circ. Physiol. 2000, 278, H1744-H1750; Sawada et al.,Circulation 2000, 101, 2030-2023; Shibata et al., Circulation 2001, 103,284-289), myocardial hypertrophy (Hoshijima et al., J. Biol. Chem. 1998,273, 7725-77230; Sah et al., J. Biol. Chem. 1996, 271, 31185-31190;Kuwahara et al., FEBS Lett. 1999, 452, 314-318; Yanazume et al., J.Biol. Chem. 2002, 277, 8618-8625), malignoma (Itoh et al., Nat. Med.1999, 5, 221-225; Genda et al., Hepatology 1999, 30, 1027-1036; Somlyoet al., Biochem. Biophys. Res. Commun. 2000, 269, 652-659),ischemia/reperfusion-induced injury (Ikeda et al., J. of Surgical Res.2003, 109, 155-160; Miznuma et al. Transplantation 2003, 75, 579-586),endothelial dysfunction (Hernandez-Perera et al., Circ. Res. 2000, 87,616-622; Laufs et al., J. Biol. Chem. 1998, 273, 24266-24271; Eto etal., Circ. Res. 2001, 89, 583-590), Crohn's Disease and colitis (Segainet al. Gastroenterology 2003, 124(5), 1180-1187), neurite outgrowth(Fournier et al. J. Neurosci. 2003, 23, 1416-1423), Raynaud's Disease(Shimokawa et al. J. Cardiovasc. Pharmacol. 2002, 39, 319-327), angina(Utsunomiya et al. Br. J. Pharmacol. 2001, 134, 1724-1730; Masumoto etal, Circulation 2002, 105, 1545-1547; Shimokawa et al, J. Cardiovasc.Pharmacol., 2002, 40, 751-761; Satoh et al., Jpn. J. Pharmacol., 2001,87, 34-40), Alzheimer's disease (Zhou et al., Science 2003, 302,1215-1218), benign prostatic hyperplasia (Rees et al., J. Urology, 2003,170, 2517-2522), and atherosclerosis (Retzer et al. FEBS Lett. 2000,466, 70-74; Ishibashi et al. Biochim. Biophys. Acta 2002, 1590,123-130). Accordingly, the development of inhibitors of ROCK kinasewould be useful as therapeutic agents for the treatment of disordersimplicated in the ROCK kinase pathway.

The Aurora proteins are a family of three highly relatedserine/threonine kinases (termed Aurora-A, -B and -C) that are essentialfor progression through the mitotic phase of cell cycle. SpecificallyAurora-A plays a crucial role in centrosome maturation and segregation,formation of the mitotic spindle and faithfull segregation ofchromosomes. Aurora-B is a chromosomal passenger protein that plays acentral role in regulating the alignment of chromosomes on themeta-phase plate, the spindle assembly checkpoint and for the correctcompletion of cytokinesis.

Overexpression of Aurora-A, -B or -C has been observed in a range ofhuman cancers including colorectal, ovarian, gastric and invasive ductadenocarcinomas. In addition amplification of the AURKA locus thatencodes for Aurora-A correlates with poor prognosis for patients withnode-negative breast cancer. Furthermore overexpression of Aurora-A hasbeen shown to transform mammalian fibroblasts, giving rise to aneuploidcells containing multipolar spindles.

A number of studies have now demonstrated that depletion or inhibitionof Aurora-A or -B in human cancer cell lines by siRNA, dominant negativeor neutralising antibodies disrupts progression through mitosis withaccumulation of cells with 4N DNA, and in some cases this is followed byendoreduplication and cell death.

Protein kinases are attractive and proven targets for new therapeuticagents to treat a range if human diseases, with examples includingGleevec and Tarceva. The Aurora kinases are especially attractive due totheir association with numerous human cancers and the role they play inpromoting proliferation of these cancer cells (Harrington et al., NatureMed., 2004, 10: 262-267).

Accordingly, there is a great need to develop inhibitors of JAK, ROCKand Aurora, preferably JAK-3, ROCK and Aurora A, protein kinases thatare useful in treating various diseases or conditions associated withJAK, ROCK and Aurora activation, particularly given the inadequatetreatments currently available for the majority of these disorders.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of JAK, ROCK and Aurora protein kinases. In certainembodiments, these compounds are effective as inhibitors of JAK-3, ROCKand Aurora protein kinases. These compounds have the general formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein R¹, R²,        R³, R⁴, X¹, X², X³, R⁵ and x are as defined below and in subsets        herein.

These compounds and pharmaceutical compositions thereof are useful fortreating or preventing a variety of disorders, including, but notlimited to, heart disease, diabetes, Alzheimer's disease,immunodeficiency disorders, inflammatory diseases, hypertension,allergic diseases, autoimmune diseases, destructive bone disorders suchas osteoporosis, proliferative disorders, infectious diseases,immunologically-mediated diseases, and viral diseases. The compositionsare also useful in methods for preventing cell death and hyperplasia andtherefore may be used to treat or prevent reperfusion/ischemia instroke, heart attacks, and organ hypoxia. The compositions are alsouseful in methods for preventing thrombin-induced platelet aggregation.The compositions are especially useful for disorders such as chronicmyelogenous leukemia (CML), acute myeloid leukemia (AML), acutepromyelocytic leukemia (APL), rheumatoid arthritis, asthma,osteoarthritis, ischemia, cancer (including, but not limited to, ovariancancer, breast cancer and endometrial cancer), liver disease includinghepatic ischemia, heart disease such as myocardial infarction andcongestive heart failure, pathologic immune conditions involving T cellactivation, and neurodegenerative disorders.

DETAILED DESCRIPTION OF THE INVENTION

1. General Description of Compounds of the Invention:

The present invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, wherein:

-   -   R¹ is T-R′ or is —Si(R′)₃;    -   R², R³, and R⁴ are each independently halogen, CN, NO₂, or V—R′;    -   X¹, X² and X³ are each independently N, or CH, wherein the        hydrogen atom of CH is optionally replaced by R⁵;    -   x is 1, 2, 3, or 4;    -   each occurrence of R⁵ is independently halogen, CN, NO₂, or        U—R′;    -   T, V, and U are each independently a bond or an optionally        substituted C₁-C₆ alkylidene chain, wherein up to two methylene        units of the chain are optionally and independently replaced by        —NR′—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR′—,        —NR′CO—, —NR′CO₂—, —SO₂NR′—, —NR′SO₂—, —CONR′NR′—, —NR′CONR′—,        —OCONR′—, —NR′NR′—, —NR′SO₂NR′—, —SO—, —SO₂—, —PO—, —PO₂—, or        —POR′—; and    -   each occurrence of R′ is independently hydrogen or an optionally        substituted group selected from a C₁-C₆ aliphatic group, a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; or two occurrences of R′ are taken        together with the atom(s) to which they are bound to form an        optionally substituted 3-12 membered saturated, partially        unsaturated, or fully unsaturated monocyclic or bicyclic ring        having 0-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur. In certain embodiments, the two occurrences        of R′ that form a ring will be on a single substituent (e.g.,        R¹, R², R³, R⁴ or on a single R⁵ substituent) and form a        monocyclic or bicyclic ring. In other embodiments, the two        occurrences of R′ are on two substituents (e.g., on two R⁵        substituents) and can form a bicyclic fused ring with the ring        to which the R⁵ substituents are attached. However, the two        occurrences of R′ do not form a tricyclic ring whether they are        a bound to a single substituent or to two separate substituents.

In certain embodiments, for compounds described directly above:

-   -   a. if R¹ is substituted cyclopentyl, x is 1, X¹ and X³ are CH,        then X² is not C—R⁵, where R⁵ is fluoro or OMe;    -   b. if R² and R³ are simultaneously H and R¹ and R⁴ are        independently selected from H or Me, x is 1, X¹ and X³ are CH,        then X² is not C—R⁵, where R⁵ is OMe, NO₂, or fluoro;    -   c. if R¹, R², R³ and R⁴ are simultaneously H, x is 1, R⁵ is        —SMe, NH₂ or an optionally substituted NH-piperidine, and X¹ and        X² are N, then X³ is not CH;    -   d. if R², R³ and R⁴ are simultaneously H, X¹, X² and X³ are CH,        and two R⁵ form a fused optionally substituted bicyclic ring        with the ring to which they are attached, then R¹ is not        CH₂CH₂N(Me)₂.    -   e. if R² and R³ are simultaneously H, R⁴ is NH₂, and X¹, X² and        X³ are CH, then R¹ is not substituted phenyl;    -   f. if R², R³ and R⁴ are simultaneously H, then R¹ is not        Si(R′)₃.    -   g. if R¹, R² and R⁴ are simultaneously H and (i) X² and X³ are        CH or CR⁵ or (ii) any one of X¹, X² or X³ are N, then R³ is not        phenyl or phenyl substituted with O-phenyl or N(Me)₂.

2. Compounds and Definitions:

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members are anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup are generally selected from halogen; —R^(o); —OR^(o); —SR^(o);phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionallysubstituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted withR^(o); —CH═CH(Ph), optionally substituted with R^(o); a 5-6 memberedheteroaryl or heterocyclic ring optionally substituted with R^(o); —NO₂;—CN; —N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o);—NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o);—NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂;—NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o);—C(O)R^(o); —C(S)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂;—OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o)) R^(o);—S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o);—C(═NH)—N(R^(o))₂; —P(O)₂R^(o); —PO(R^(o))₂; —OPO(R^(o))₂; or—(CH₂)₀₋₂NHC(O)R^(o); wherein each independent occurrence of R^(o) isselected from hydrogen, optionally substituted C₁₋₆ aliphatic, anunsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl,—O(Ph), or —CH₂(Ph), or, notwithstanding the definition above, twoindependent occurrences of R^(o), on the same substituent or differentsubstituents, taken together with the atom(s) to which each R^(o) groupis bound, to form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

Optional substituents on the aliphatic group of R^(o) are selected fromNH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH,O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄aliphatic, wherein each of the foregoingC₁₋₄aliphatic groups of R^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the saturated carbon of an aliphatic or heteroaliphaticgroup, or of a non-aromatic heterocyclic ring are selected from thoselisted above for the unsaturated carbon of an aryl or heteroaryl groupand additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group.

Unless otherwise defined above and herein, optional substituents on thenitrogen of a non-aromatic heterocyclic ring are generally selected from—R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺,—SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ ishydrogen, an optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted —O(Ph), optionallysubstituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionallysubstituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl orheterocyclic ring having one to four heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur, or, notwithstanding the definitionabove, two independent occurrences of R⁺, on the same substituent ordifferent substituents, taken together with the atom(s) to which each R⁺group is bound, form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

Optional substituents on the aliphatic group or the phenyl ring of R⁺are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H,—CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic),wherein each of the foregoing C₁₋₄aliphatic groups of R⁺ isunsubstituted.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

The term “protecting group”, as used herein, refers to an agent used totemporarily block one or more desired reactive sites in amultifunctional compound. In certain embodiments, a protecting group hasone or more, or preferably all, of the following characteristics: a)reacts selectively in good yield to give a protected substrate that isstable to the reactions occurring at one or more of the other reactivesites; and b) is selectively removable in good yield by reagents that donot attack the regenerated functional group. Exemplary protecting groupsare detailed in Greene, T. W., Wuts, P. G in “Protective Groups inOrganic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999,the entire contents of which are hereby incorporated by reference. Theterm “nitrogen protecting group”, as used herein, refers to an agentsused to temporarily block one or more desired nitrogen reactive sites ina multifunctional compound. Preferred nitrogen protecting groups alsopossess the characteristics exemplified above, and certain exemplarynitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, ThirdEdition, John Wiley & Sons, New York: 1999, the entire contents of whichare hereby incorporated by reference.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which they are bound to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which each variable is bound include,but are not limited to the following: a) two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein) thatare bound to the same atom and are taken together with that atom to forma ring, for example, N(R^(o))₂, where both occurrences of R^(o) aretaken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(o) (or R⁺, R, R′ or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of OR^(o)

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, R, R′ or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

3. Description of Exemplary Compounds:

As described generally above, R¹ is T-R′, or is —Si(R′)₃. In certainembodiments, when R¹ is T-R′, T is an optionally substitutedC₁-C₆alkylidene chain wherein up to two methylene units are optionallyand independently replaced with —O—, —S—, —NR′—, —OCO—, —COO—, —SO₂— or—CO—, and R′ is hydrogen, C₁-C₄-alkyl, or an optionally substituted 5-or 6-membered aryl or heteroaryl group. In other embodiments of R¹, R′may additionally be C₁-C₄-aliphatic. In other embodiments, when R¹ is—Si(R′)₃, R′ is hydrogen, C₁-C₄-alkyl, or an optionally substituted 5-or 6-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In still other embodiments, R¹ is hydrogen,C₁-C₄alkyl, —COR′, —SO₂R′, or —Si(R′)₃. In yet other embodiments, R¹ ishydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl(Ts), t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), ortriethylsilyl (TES). Exemplary R¹ groups are also depicted in Tables 1and 2 herein.

As described generally above, R², R³, and R⁴ are each independentlyhalogen, CN, NO₂, or V—R′. In certain embodiments, R², R³, and R⁴ areeach independently hydrogen, R′, halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂,—OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NR′COR′, —CON(R′)₂, —SO₂N(R′)₂,—CONR′(CH₂)₂N(R′)₂, —CONR′(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′,O(CH₂)₃OR′, O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, or—O(CH₂)₄N(R′)₂. In other embodiments, R², R³, and R⁴ are eachindependently Cl, Br, F, —CN, —COOH, —COOMe, —NH₂, —N(CH₃)₂, —N(Et)₂,—N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂,—SO₂N(Me)₂, or an optionally substituted group selected from C₁-C₄alkyl,C₁-C₄alkyloxy, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In still other embodiments, R², R³, and R⁴ are eachhydrogen. In other embodiments, one of R², R³, or R⁴ is hydrogen. In yetother embodiments, two of R², R³, or R⁴ is hydrogen. In yet otherembodiments, R² and R⁴ are both hydrogen, and R³ is halogen, CN, NO₂, orV—R′. In still other embodiments, R² and R⁴ are both hydrogen, and R³ isan optionally substituted group selected from a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-12 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In yet other embodiments, R² and R⁴ areboth hydrogen, and R³ is an optionally substituted 5- or 6-memberedsaturated, partially unsaturated, or fully unsaturated ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur. Inyet other embodiments, R² and R⁴ are both hydrogen, and R³ is anoptionally substituted ring selected from phenyl, pyridyl, pyrimidinyl,thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl,pyrazinyl, thiadiazolyl, or oxadiazolyl. In yet other embodiments, whenR¹, R² and R⁴ are H, then R³ is not an optionally substituted phenyl. Inyet other embodiments, when R¹, R² and R⁴ are H, then R³ is not an aryl,heteroaryl, carbocyclyl or heterocyclyl ring. Exemplary R², R³, and R⁴groups also include those shown below in Tables 1 and 2.

As described above, R², R³, and R⁴ are each optionally substituted, andin certain embodiments, R², R³, and R⁴ are each optionally andindependently substituted with z occurrences of R⁶, wherein z is 0-5 andR⁶ is ═O, ═NR″, ═S, halogen, —CN, —NO₂, or Z-R″, wherein Z is a bond oran optionally substituted C₁-C₆ alkylidene chain, wherein up to twomethylene units of the chain are optionally and independently replacedby —NR″—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—,—NR″CO₂—, —SO₂NR″—, —NR″SO₂—, —CONR″NR″—, —NR″CONR″—, —OCONR″—,—NR″NR″—, —NR″SO₂NR″—, —SO—, —SO₂—, —PO—, —PO₂— or —POR″—, and and eachoccurrence of R^(″) is independently hydrogen or an optionallysubstituted C₁-C₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R″ are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In other embodiments, z is 0,1, 2, or 3, and each occurrence of R⁶ is independently hydrogen, R″,—CH₂R″, halogen, CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″,—CH₂SR″, —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂,—CONR″(CH₂)₂N(R″)₂, —CONR(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″,O(CH₂)₃OR″, O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂,—NR″CH(CH₂OH)R″, —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″,—NR″(CH₂)₂R″, —NR″(CH₂)₃R″, —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂,—NR″(CH₂)₂N(R″)₂, —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″,—NR″(CH₂)₂OR″, —NR″(CH₂)₃OR″, or —NR″(CH₂)₄OR″. In other embodiments, R⁶may additionally be —NR″CH(CH₃)R″. In still other embodiments, z is 1,2, or 3 and each occurrence of R⁶ is independently F, Cl, Br, CN, OH,NH₂, —CH₂OH, C₁-C₆alkyl, —O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl),—CO(C₁-C₆alkyl), —COO(C₁-C₆alkyl), —NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂,—CON(C₁-C₆alkyl), —SO₂(C₁-C₆alkyl), —SO₂phenyl, phenyl, benzyl,—N(C₁-C₆alkyl)₂, or —S(C₁-C₆alkyl), wherein each of the foregoingphenyl, benzyl, and C₁-C₆alkyl groups is independently and optionallysubstituted, and wherein each of the foregoing C₁-C₆alkyl groups islinear, branched, or cyclic. Additional exemplary R⁶ groups are depictedin Table 1.

As described generally above for compounds of formula I, X¹, X² and X³are each independently N, or CH, wherein the hydrogen atom of CH isoptionally replaced by R⁵. In certain embodiments, two of X¹, X², or X³is N, and the remaining one of X¹, X², or X³ is CH, wherein the hydrogenatom of CH is optionally replaced by R⁵. In certain other embodiments,one of X¹, X², or X³ is N, and the remaining two of X¹, X², or X³ is CH,wherein the hydrogen atom of CH is optionally replaced by R⁵. In yetother embodiments, each of X¹, X² and X³ is CH, wherein the hydrogenatom of CH is optionally replaced by R⁵. In certain other exemplaryembodiments, compounds have one of formulae I-A, I-B, I-C or I-D:

In other embodiments, compounds have formula I-E:

As described generally for compounds of formula I above, x is 1, 2, 3,or 4; and each occurrence of R⁵ is independently halogen, CN, NO₂, orU—R′, wherein each occurrence of U is independently a bond or anoptionally substituted C₁-C₆ alkylidene chain, wherein up to twomethylene units of the chain are optionally and independently replacedby —NR′—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR′—, —NR′CO—,—NR′CO₂—, —SO₂NR′—, —NR′SO₂—, —CONR′NR′—, —NR′CONR′—, —OCONR′—,—NR′NR′—, —NR′SO₂NR′—, —SO—, —SO₂—, —PO—, —PO₂—, or —POR′—; and eachoccurrence of R^(′) is independently hydrogen or an optionallysubstituted C₁-C₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R′, are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In certain embodiments, eachoccurrence of R⁵ is independently hydrogen, R′, —CH₂R′, halogen, CN,NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′,—NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′, —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂,—CONR′(CH₂)₂N(R′)₂, —CONR′(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′,O(CH₂)₃OR′, O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,—NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′,—NR′(CH₂)₃R′, —NR′(CH₂)₄R′, —NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂,—NR′(CH₂)₃N(R′)₂, —NR′(CH₂)₄N(R′)₂, —NR′(CH₂)OR′, —NR′(CH₂)₂OR′,—NR′(CH₂)₃OR′, or —NR′(CH₂)₄OR′. In certain embodiments, R⁵ may also be—NR′CH(CH₃)R′, NR′CH(CF₃)R′, —NR′CH(CH₃)C(O)OR′, —NR′CH(CF₃)C(O)OR′,—NR′CH(CH₂CH₃)R′, —NR′CH₂C(O)N(R′)₂, —NR′CH(CH₃)C(O)N(R′)₂,NR′CH(CF₃)C(O)N(R′)₂, —NR′CH(CH₂CH₃)C(O)N(R′)₂,—NR′CH(CH(CH₃)₂)C(O)N(R′)₂, —NR′CH(C(CH₃)₃)C(O)N(R′)₂,—NR′CH(CH₂CH(CH₃)₂)C(O)N(R′)₂, —NR′CH(CH₂OR⁹)C(O)N(R′)₂ or—NR′CH(CH₂CH₂N(Me)₂)C(O)N(R′)₂. In certain exemplary embodiments, x is1, 2, or 3, and at least one occurrence of R⁵ is —N(R′)₂,—NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′,NR′(CH₂)N(R′)₂, or —NR′(CH₂)₂N(R′)₂. In other embodiments, x is 1, 2, or3, and at least one occurrence of R⁵ is —OR′. In other embodiments, x is1, 2, or 3, and at least one occurrence of R⁵ is halogen. In yet otherembodiments, x is 1, 2, or 3, and at least one occurrence of R⁵ is—NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′, —NR′CH(CH₂OH)R′,—NR′CH(CH₂OMe)R′, —NR′CH(CH₂OEt)R′, —NR′CH(CH₂OCF₃)R′,—NR′CH(CH₂CH₂OH)R′, —NR′CH(CH₂CH₂OMe)R′, —NR′CH(CH₂CH₂OEt)R′,—NR′CH(CH₂CH₂OCF₃)R′, —NR′CH(CH₃)C(O)OR′, —NR′CH(CF₃)C(O)OR′,—NR′CH(CH₃)C(O)N(R′)₂, —NR′CH(CF₃)C(O)N(R′)₂, —NR′CH(CH₂CH₃)C(O)N(R′)₂,—NR′CH(CH₂OH)C(O)N(R′)₂, —NR′CH(CH₂OMe)C(O)N(R′)₂,—NR′CH(CH₂OEt)C(O)N(R′)₂ or —NR′CH(CH₂OCF₃)C(O)N(R′)₂, wherein R′ is anoptionally substituted C₁-C₄ aliphatic; NHCH₂C(O)NHR′,—NHCH(CH₃)C(O)NHR′, —NHCH(CH₂CH₃)C(O)NHR′, —NHCH(CH(CH₃)₂)C(O)NHR′,—NHCH(C(CH₃)₃)C(O)NHR′, —NHCH(CH₂CH(CH₃)₂)C(O)NHR′,—NHCH(CH₂OH)C(O)NHR′, —NHCH(CH₂OMe)C(O)NHR′ or—NHCH(CH₂CH₂N(Me)₂)C(O)NHR′, wherein R′ is an optionally substitutedC₁-C₄ aliphatic; —NHR′, —NH(CH₂)R′, —NH(CH₂)₂R′, —NHCH(CH₃)R′,—NHCH₂C(O)NHR′, —NHCH(CH₃)C(O)NHR′, —NHCH(CH₂CH₃)C(O)NHR′,—NHCH(CH(CH₃)₂)C(O)NHR′, —NHCH(C(CH₃)₃)C(O)NHR′,—NHCH(CH₂CH(CH₃)₂)C(O)NHR′, —NHCH(CH₂OH)C(O)NHR′, —NHCH(CH₂OMe)C(O)NHR′or —NHCH(CH₂CH₂N(Me)₂)C(O)NHR′, wherein R′ is an optionally substitutedC₁-C₄ aliphatic; —NHCH(CH₃)R′, wherein R′ is optionally substitutedphenyl; H, halogen, CH₃, CF₃, COOH, COOMe or OR′, wherein R′ is C₁-C₄aliphatic.

In still other embodiments, x is 1, 2, or 3, and at least one occurrenceof R⁵ is an optionally substituted C₁-C₆ aliphatic group, a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In yet other embodiments, x is 1 or 2, and each occurrence of R⁵ isindependently halogen, R′, CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂,—(CH₂)₂NO₂, CON(R′)₂, —CH₂CON(R′)₂, —(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′,—(CH₂)₂COOR′, —SO₂N(R′)₂, —CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′,—CH₂NR′SO₂R′, —(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂,—(CH₂)₂NR′CON(R′)₂, —NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂,—(CH₂)₂NR′SO₂N(R′)₂, —COCOR′, —CH₂COCOR′, —(CH₂)₂COCOR′, —N(R′)₂,—CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′, —CH₂OR′, —(CH₂)₂OR′, —NR′COR′,—NR′COCH₂R′, —NR′CO(CH₂)₂R′, —CH₂NR′COR′, or —(CH₂)₂NR′COR′. In yetother embodiments, R⁵ is CN, —CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂,—(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂, —SO₂N(R′)₂, —N(R′)₂, or R′. Instill other embodiments, each occurrence of R⁵ is independentlyhydrogen, halogen, CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂, —(CH₂)₂NO₂,—CONH₂, —CON(C₁-C₄alkyl), —SO₂NH₂, —SO₂N(C₁-C₄alkyl), NH₂,—N(C₁-C₄alkyl), —OH, —O(C₁-C₄alkyl), —CH₂OH, —CH₂O(C₁-C₄alkyl), or anoptionally substituted 5- or 6-membered unsaturated ring wherein 0-3ring carbon atoms is optionally replaced by oxygen, sulfur, or nitrogen.

As described generally for compounds of formula I above, R⁵ isoptionally substituted with y occurrences of R⁷, wherein y is 0-5 and R⁷is ═O, ═NR″, ═S, halogen, —CN, —NO₂, or W—R″, wherein W is a bond or anoptionally substituted C₁-C₆ alkylidene chain, wherein up to twomethylene units of the chain are optionally and independently replacedby —NR″—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—,—NR″CO₂—, —SO₂NR″—, —NR″SO₂—, —CONR″NR″—, —NR″CONR″—, —OCONR″—,—NR″NR″—, —NR″SO₂NR″—, —SO—, —SO₂—, —PO—, —PO₂—, or —POR″—, and and eachoccurrence of R^(″) is independently hydrogen or an optionallysubstituted C₁-C₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R^(″), are taken together withthe atom(s) to which they are bound to form an optionally substituted3-12 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In other embodiments, y is 0,1, 2, or 3, and each occurrence of R⁷ is independently hydrogen, R″,—CH₂R″, halogen, CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″,—CH₂SR″, —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂,—CONR″(CH₂)₂N(R″)₂, —CONR′(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″,O(CH₂)₃OR″, O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂,—NR″CH(CH₂OH)R″, —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″,—NR″(CH₂)₃R″, —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,—NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,—NR″(CH₂)₃OR″, or —NR″(CH₂)₄OR″. In certain embodiments, R⁷ may also be—NR′CH(CH₃)R′. In other embodiments, y is 1, 2, or 3 and each occurrenceof R⁷ is independently F, Cl, Br, CN, OH, NH₂, —CH₂OH, C₁-C₆alkyl,—O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl), —COO(C₁-C₆alkyl),—NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl), —SO₂(C₁-C₆alkyl),—SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or —S(C₁-C₆alkyl), whereineach of the foregoing phenyl, benzyl, and C₁-C₆alkyl groups isindependently and optionally substituted, and wherein each of theforegoing C₁-C₆alkyl groups is linear, branched, or cyclic. Additionalexemplary R⁷ groups are depicted in Table 1.

In still other embodiments, x is 1, 2, or 3; at least one occurence ofR⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,—NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′,—NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic group or a3-8-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; ortwo occurrences of R^(′) are taken together with the atom(s) to whichthey are bound to form an optionally substituted 3-12 memberedsaturated, partially unsaturated, or fully unsaturated monocyclic orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein each occurrence of R′ is optionallysubstituted with y occurrences of R⁷. In certain embodiments, R′ ishydrogen, C₁-C₆alkyl optionally substituted with 1-3 occurrences of R⁷,or is a 5-10-membered monocyclic or bicyclic saturated, partiallyunsaturated or fully unsaturated ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein thering is optionally substituted with 1-3 occurrences of R⁷. In otherembodiments, R′ is hydrogen, C₁-C₄alkyl optionally substituted with 1-3occurrences of R⁷, or is a ring selected from:

-   -   wherein y and R⁷ are described generally and in subsets above.        In another embodiment, R′ may be

xLvii, wherein y and R⁷ are described generally and in subsets above.

In yet other embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′are taken together with the nitrogen atom to which they are bound toform an optionally substituted 3-10-membered monocyclic or bicyclicheterocyclic ring. In certain embodiments, the ring is selected from:

-   -   wherein y and R⁷ are described generally and in subsets above.

Certain additional subsets of compounds of general formula I include:

I. Compounds of Formula I-A:

-   -   wherein R¹, R², R³, R⁴, R⁵ and x are each described generally        above and in subsets described above and herein.

In some embodiments, for compounds of formula I-A:

-   -   a. R¹ is:        -   i. T-R′, wherein T is a bond or an optionally substituted            C₁-C₆alkylidene chain wherein up to two methylene units are            optionally and independently replaced with —O—, —S—, —NR′—,            —OCO—, —COO—, —SO₂— or —CO—, and R′ is hydrogen,            C₁-C₄-alkyl, or an optionally substituted 5- or 6-membered            aryl or heteroaryl group, or        -   ii. —Si(R′)₃, wherein R′ is hydrogen, C₁-C₄-alkyl, or an            optionally substituted 5- or 6-membered saturated, partially            unsaturated, or fully unsaturated monocyclic ring having 0-3            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;    -   b. R², R³, and R⁴ are each independently hydrogen, R′, halogen,        CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,        —COOR′, —NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′, —CON(R′)₂,        —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂, —CONR′(CH₂)₃N(R′)₂,        —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′, O(CH₂)₄OR′,        —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, or —O(CH₂)₄N(R′)₂; wherein R²,        R³, and R⁴ are each optionally substituted with z occurrences of        R⁶, wherein z is 0-5 and R⁶ is ═O, ═NR″, ═S, halogen, —CN, —NO₂,        or Z-R″, wherein Z is a bond or an optionally substituted C₁-C₆        alkylidene chain, wherein up to two methylene units of the chain        are optionally and independently replaced by —NR″—, —S—, —O—,        —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO₂—,        —SO₂NR″—, —NR″SO₂—, —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—,        —NR″SO₂NR″—, —SO—, —SO₂—, —PO—, —PO₂—, or —POR″—, and each        occurrence of R^(″) is independently hydrogen or an optionally        substituted C₁-C₆ aliphatic group, a 3-8-membered saturated,        partially unsaturated, or fully unsaturated monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, or an 8-12 membered saturated, partially        unsaturated, or fully unsaturated bicyclic ring system having        0-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or two occurrences of R″ are taken together with the        atom(s) to which they are bound to form an optionally        substituted 3-12 membered saturated, partially unsaturated, or        fully unsaturated monocyclic or bicyclic ring having 0-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   c. each occurrence of R⁵ is independently hydrogen, R′, —CH₂R′,        halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′,        —CH₂SR′, —COOR′, —NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′,        —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂,        —CONR(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′,        O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′,        —NR′(CH₂)₃R′, —NR′(CH₂)₄R′, —NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂,        —NR′(CH₂)₃N(R′)₂, —NR′(CH₂)₄N(R′)₂, —NR′(CH₂)OR′, —NR′(CH₂)₂OR′,        —NR′(CH₂)₃OR′, or —NR′(CH₂)₄OR′, wherein R⁵ is optionally        substituted with y occurrences of R⁷, wherein y is 0-5 and R⁷ is        ═O, ═NR″, ═S, halogen, —CN, —NO₂, or W—R′, wherein W is a bond        or an optionally substituted C₁-C₆ alkylidene chain, wherein up        to two methylene units of the chain are optionally and        independently replaced by —NR″—, —S—, —O—, —CS—, —CO₂—, —OCO—,        —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO₂—, —SO₂NR″—, —NR″SO₂—,        —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—, —NR″SO₂NR″—, —SO—,        —SO₂—, —PO—, —PO₂—, or —POR″—, and and each occurrence of R^(″)        is independently hydrogen or an optionally substituted C₁-C₆        aliphatic group, a 3-8-membered saturated, partially        unsaturated, or fully unsaturated monocyclic ring having 0-3        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or an 8-12 membered saturated, partially unsaturated, or        fully unsaturated bicyclic ring system having 0-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; or two        occurrences of R″ are taken together with the atom(s) to which        they are bound to form an optionally substituted 3-12 membered        saturated, partially unsaturated, or fully unsaturated        monocyclic or bicyclic ring having 0-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur.

In still other embodiments, for compounds of formula I-A:

-   -   a. R¹ is hydrogen, C₁-C₄alkyl, —COR′, —SO₂R′, or —Si(R′)₃;    -   b. R², R³, and R⁴ are each independently Cl, Br, F, —CN, —COOH,        —COOMe, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,        —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂N(Me)₂, or an        optionally substituted group selected from C₁-C₄alkyl,        C₁-C₄alkyloxy, a 3-8-membered saturated, partially unsaturated,        or fully unsaturated monocyclic ring having 0-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or an        8-12 membered saturated, partially unsaturated, or fully        unsaturated bicyclic ring system having 0-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; wherein        R², R³, and R⁴ are each independently and optionally substituted        with z occurrences of R⁶, wherein z is 0, 1, 2, or 3, and each        occurrence of R⁶ is independently hydrogen, R″, —CH₂R″, halogen,        CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″,        —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂,        —CONR″(CH₂)₂N(R″)₂, —CONR(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂,        —O(CH₂)₂OR″, O(CH₂)₃OR″, O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂,        —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂, —NR″CH(CH₂OH)R″,        —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″, —NR″(CH₂)₃R″,        —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″;    -   c. each occurrence of R⁵ is independently hydrogen, R′, —CH₂R′,        halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′,        —CH₂SR′, —COOR′, —NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′,        —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂,        —CONR(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′,        O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′,        —NR′(CH₂)₃R′, —NR′(CH₂)₄R′, —NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂,        —NR′(CH₂)₃N(R′)₂, —NR′(CH₂)₄N(R′)₂, —NR′(CH₂)OR′, —NR′(CH₂)₂OR′,        —NR′(CH₂)₃OR′, or —NR′(CH₂)₄OR′, wherein R⁵ is optionally        substituted with y occurrences of R⁷, wherein y is 0, 1, 2, or        3, and each occurrence of R⁷ is independently hydrogen, R″,        —CH₂R″, halogen, CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″,        —SR″, —CH₂SR″, —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂,        —SO₂N(R″)₂, —CONR″(CH₂)₂N(R″)₂, —CONR(CH₂)₃N(R″)₂,        —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″, O(CH₂)₃OR″, O(CH₂)₄OR″,        —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂, —NR″CH(CH₂OH)R″,        —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″, —NR″(CH₂)₃R″,        —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR″(CH₂)₄OR″.

In other embodiments, for compounds of formula I-A and subsets describeddirectly above, R¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl,n-butyl, p-toluenesulfonyl (Ts), t-butyldimethylsilyl (TBS),triisopropylsilyl (TIPS), or triethylsilyl (TES).

In still other embodiments, for compounds of formula I-A and subsetsdescribed directly above, R², R³, and R⁴ are each hydrogen. In otherembodiments, one of R², R³, or R⁴ is hydrogen. In yet other embodiments,two of R², R³, or R⁴ is hydrogen. In yet other embodiments, R² and R⁴are both hydrogen, and R³ is halogen, CN, NO₂, or V—R′. In still otherembodiments, R² and R⁴ are both hydrogen, and R³ is an optionallysubstituted group selected from a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In yet other embodiments, R² and R⁴ are bothhydrogen, and R³ is an optionally substituted 5- or 6-memberedsaturated, partially unsaturated, or fully unsaturated ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur. Inyet other embodiments, R² and R⁴ are both hydrogen, and R³ is anoptionally substituted ring selected from phenyl, pyridyl, pyrimidinyl,thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl,pyrazinyl, thiadiazolyl, or oxadiazolyl. In yet other embodiments, R³ isselected from H, Cl, Br, F, —CN, —COOH, —COOMe, —NH₂, —N(R′)₂, —NO₂,—OR′, —CON(R′)₂, —COOR′, —OH, —SR′, —C(R′)₂OR′, —N(R′)COR′,—N(R′)C(O)OR′, —SO₂NH₂, —SO₂N(R′)₂, or an optionally substituted groupselected from C₁-C₄ aliphatic, C₁-C₄ alkyloxy or —C≡C—C₁-C₄ aliphatic.In a further embodiment, R² and R⁴ are both hydrogen and R³ is selectedfrom the immediately preceding list.

In other embodiments, for compounds of formula I-A and subsets describeddirectly above, R², R³, and R⁴ are each independently and optionallysubstituted with z occurrences of R⁶, wherein z is 1, 2, or 3 and eachoccurrence of R⁶ is independently F, Cl, Br, CN, OH, NH₂, —CH₂OH,C₁-C₆alkyl, —O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl),—COO(C₁-C₆alkyl), —NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl),—SO₂(C₁-C₆alkyl), —SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or—S(C₁-C₆alkyl), wherein each of the foregoing phenyl, benzyl, andC₁-C₆alkyl groups is independently and optionally substituted, andwherein each of the foregoing C₁-C₆alkyl groups is linear, branched, orcyclic.

In certain exemplary embodiments, for compounds of formula I-A andsubsets described directly above, x is 1, 2, or 3, and at least oneoccurrence of R¹ is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′,—NR′(CH₂)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, or —NR′(CH₂)₂N(R′)₂. In otherembodiments, x is 1, 2, or 3, and at least one occurrence of R⁵ is —OR′.In yet other embodiments, x is 1, 2, or 3, and at least one occurrenceof R⁵ is —NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′. In still otherembodiments, x is 1, 2, or 3, and at least one occurrence of R⁵ is anoptionally substituted C₁-C₆ aliphatic group, a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-12 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In still other embodiments, for compounds of formula I-A and subsetsdescribed directly above, R⁵ is optionally substituted with yoccurrences of R⁷, wherein y is 1, 2, or 3 and each occurrence of R⁷ isindependently F, Cl, Br, CN, OH, NH₂, —CH₂OH, C₁-C₆alkyl,—O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl), —COO(C₁-C₆alkyl),—NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl), —SO₂(C₁-C₆alkyl),—SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or —S(C₁-C₆alkyl), whereineach of the foregoing phenyl, benzyl, and C₁-C₆alkyl groups isindependently and optionally substituted, and wherein each of theforegoing C₁-C₆alkyl groups is linear, branched, or cyclic. In yet otherembodiments, for compounds of formula I-A and subsets described directlyabove, x is 1, 2, or 3; at least one occurence of R⁵ is —N(R′)₂,—NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′,NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′, or—NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic group or a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; or two occurrences of R′, aretaken together with the atom(s) to which they are bound to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein eachoccurrence of R′ is optionally substituted with y occurrences of R⁷. Incertain embodiments, R′ is hydrogen, C₁-C₆alkyl optionally substitutedwith 1-3 occurrences of R⁷, or is a 5-10-membered monocyclic or bicyclicsaturated, partially unsaturated or fully unsaturated ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein the ring is optionally substituted with 1-3 occurrences of R⁷.In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionally substitutedwith 1-3 occurrences of R⁷, or is a ring selected from (i)-(xLvi) or(xLvii) described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ andthe two occurrences of R′ are taken together with the nitrogen atom towhich they are bound to form an optionally substituted 3-10-memberedmonocyclic or bicyclic heterocyclic ring. In certain embodiments, thering is selected from (a)-(o) described in [0060].

In yet other embodiments, x is 1 and compounds have general formulaI-A-i:

-   -   wherein R¹, R², R³, and R⁴ are described generally and in        subsets above and herein, and R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′,        —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂,        —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′, or        —NR′CO(CH₂)₂R′, and R′ is a C₁-C₆aliphatic group or a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; or two occurrences of R′, are taken        together with the atom(s) to which they are bound to form an        optionally substituted 3-12 membered saturated, partially        unsaturated, or fully unsaturated monocyclic or bicyclic ring        having 0-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein each occurrence of R′ is optionally        substituted with y occurrences of R⁷. In some embodiments, R⁵ is        N(R′)₂. In certain embodiments, R′ is hydrogen, C₁-C₆alkyl        optionally substituted with 1-3 occurrences of R⁷, or is a        5-10-membered monocyclic or bicyclic saturated, partially        unsaturated or fully unsaturated ring having 0-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        the ring is optionally substituted with 1-3 occurrences of R⁷.        In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionally        substituted with 1-3 occurrences of R⁷, or is a ring selected        from (i)-(xLvi) or (xLvii) described in [0059]. In yet other        embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are        taken together with the nitrogen atom to which they are bound to        form an optionally substituted 3-10-membered monocyclic or        bicyclic heterocyclic ring. In certain embodiments, the ring is        selected from (a)-(o) described in [0060].

In still other embodiments, x is 1 and compounds have general formulaI-A-ii:

wherein R¹, R², R³, and R⁴ are described generally and in subsets aboveand herein, and R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′,—NR′(CH₂)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′,—NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphaticgroup or a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R^(′), are taken together withthe atom(s) to which they are bound to form an optionally substituted3-12 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein each occurrence of R′is optionally substituted with y occurrences of R⁷. In some embodiments,R⁵ is N(R′)₂. In certain embodiments, for each of the subsets describedabove, R′ is hydrogen, C₁-C₆alkyl optionally substituted with 1-3occurrences of R⁷, or is a 5-10-membered monocyclic or bicyclicsaturated, partially unsaturated or fully unsaturated ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein the ring is optionally substituted with 1-3 occurrences of R⁷.In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionally substitutedwith 1-3 occurrences of R⁷, or is a ring selected from (i)-(xLvi) or(xLvii) described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ andthe two occurrences of R′ are taken together with the nitrogen atom towhich they are bound to form an optionally substituted 3-10-memberedmonocyclic or bicyclic heterocyclic ring. In certain embodiments, thering is selected from (a)-(o) described in [0060].

In still other embodiments, R¹, R², R³ and R⁴ are each hydrogen andcompounds of formula I-A-iii are provided:

wherein x is 1, 2, or 3; and at least one occurence of R⁵ is —N(R′)₂,—NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′,NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′, or—NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic group optionally substitutedwith y occurrences of R⁷, or is a ring selected from (i)-(xLvi) or(xLvii) described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ andthe two occurrences of R′ are taken together with the nitrogen atom towhich they are bound to form an optionally substituted 3-10-memberedmonocyclic or bicyclic heterocyclic ring. In certain embodiments, thering is selected from (a)-(o) described in [0060].

In still other embodiments, R¹, R², R³ and R⁴ are each hydrogen, and xis 1, and compounds of formula I-A-iv are provided:

wherein R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,—NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′,—NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic groupoptionally substituted with y occurrences of R⁷ or is a ring selectedfrom (i)-(xLvi) or (xLvii) described in [0059]. In yet otherembodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are takentogether with the nitrogen atom to which they are bound to form anoptionally substituted 3-10-membered monocyclic or bicyclic heterocyclicring. In certain embodiments, the ring is selected from (a)-(o)described in [0060].

In still other embodiments, R¹, R², R³ and R⁴ are each hydrogen, x is 1,and compounds of formula I-A-v are provided:

wherein R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,—NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′,—NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic groupoptionally substituted with y occurrences of R⁷ or is a ring selectedfrom (i)-(xLvi) or (xLvii) described in [0059]. In yet otherembodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are takentogether with the nitrogen atom to which they are bound to form anoptionally substituted 3-10-membered monocyclic or bicyclic heterocyclicring. In certain embodiments, the ring is selected from (a)-(o)described in [0060].

In still other embodiments, R¹, R², and R⁴ are each hydrogen, andcompounds of formula I-A-vi are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;        x is 1, 2, or 3; and at least one occurence of R⁵ is —N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′,        NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′,        or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic group optionally        substituted with y occurrences of R⁷, or is a ring selected from        (i)-(xLvi) or (xLvii) described in [0059]. In yet other        embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are        taken together with the nitrogen atom to which they are bound to        form an optionally substituted 3-10-membered monocyclic or        bicyclic heterocyclic ring. In certain embodiments, the ring is        selected from (a)-(o) described in [0060].

In yet other embodiments for compounds described directly above, R³ isan optionally substituted 5- or 6-membered saturated, partiallyunsaturated, or fully unsaturated ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In yet otherembodiments, R³ is an optionally substituted ring selected from phenyl,pyridyl, pyrimidinyl, thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl,pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, or oxadiazolyl. Asdescribed generally above, R³ is optionally substituted with zoccurrences of R⁶. In certain embodiments, wherein z is 0, 1, 2, or 3,and each occurrence of R⁶ is independently hydrogen, R″, —CH₂R″,halogen, CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″,—COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂, —CONR″(CH₂)₂N(R″)₂,—CONR′(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″, O(CH₂)₃OR″,O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂,—NR″CH(CH₂OH)R″, —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″,—NR″(CH₂)₃R″, —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,—NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,—NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″.

In still other embodiments, R¹, R², R³ and R⁴ are each hydrogen, and xis 1, and compounds of formula I-A-vii are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′,        —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂,        —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′, or        —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic group optionally        substituted with y occurrences of R⁷, or is a ring selected from        (i)-(xLvi) or (xLvii) described in [0059]. In yet other        embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are        taken together with the nitrogen atom to which they are bound to        form an optionally substituted 3-10-membered monocyclic or        bicyclic heterocyclic ring. In certain embodiments, the ring is        selected from (a)-(o) described in [0060].

In yet other embodiments for compounds described directly above, R³ isan optionally substituted 5- or 6-membered saturated, partiallyunsaturated, or fully unsaturated ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In yet otherembodiments, R³ is an optionally substituted ring selected from phenyl,pyridyl, pyrimidinyl, thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl,pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, or oxadiazolyl. Asdescribed generally above, R³ is optionally substituted with zoccurrences of R⁶. In certain embodiments, wherein z is 0, 1, 2, or 3,and each occurrence of R⁶ is independently hydrogen, R″, —CH₂R″,halogen, CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″,—COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂, —CONR″(CH₂)₂N(R″)₂,—CONR′(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″, O(CH₂)₃OR″,O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂,—NR″CH(CH₂OH)R″, —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″,—NR″(CH₂)₃R″, —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,—NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,—NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″.

In still other embodiments, R¹, R², R³ and R⁴ are each hydrogen, x is 1,and compounds of formula I-A-viii are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′,        —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂,        —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′, or        —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic group optionally        substituted with y occurrences of R⁷, or is a ring selected from        (i)-(xLvi) or (xLvii) described in [0059]. In yet other        embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are        taken together with the nitrogen atom to which they are bound to        form an optionally substituted 3-10-membered monocyclic or        bicyclic heterocyclic ring. In certain embodiments, the ring is        selected from (a)-(o) described in [0060].

In yet other embodiments for compounds described directly above, R³ isan optionally substituted 5- or 6-membered saturated, partiallyunsaturated, or fully unsaturated ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In yet otherembodiments, R³ is an optionally substituted ring selected from phenyl,pyridyl, pyrimidinyl, thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl,pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl; or oxadiazolyl. Asdescribed generally above, R³ is optionally substituted with zoccurrences of R⁶. In certain embodiments, wherein z is 0, 1, 2, or 3,and each occurrence of R⁶ is independently hydrogen, R″, —CH₂R″,halogen, CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″,—COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂, —CONR″(CH₂)₂N(R″)₂,—CONR′(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″, O(CH₂)₃OR″,O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂,—NR″CH(CH₂OH)R″, —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″,—NR″(CH₂)₃R″, —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,—NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,—NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″.

Certain additional subsets of compounds of general formula I include:

II. Compounds of Formula I-C:

-   -   wherein R¹, R², R³, R⁴, R⁵ and x are each described generally        above and in subsets described above and herein.

In some embodiments, for compounds of formula I-C:

-   -   a. R¹ is:        -   i. T-R′, wherein T is a bond or an optionally substituted            C₁-C₆alkylidene chain wherein up to two methylene units are            optionally and independently replaced with —O—, —S—, —NR′—,            —OCO—, —COO—, —SO₂— or —CO—, and R′ is hydrogen,            C₁-C₄-alkyl, or an optionally substituted 5- or 6-membered            aryl or heteroaryl group, or        -   ii. —Si(R′)₃, wherein R′ is hydrogen, C₁-C₄-alkyl, or an            optionally substituted 5- or 6-membered saturated, partially            unsaturated, or fully unsaturated monocyclic ring having 0-3            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;    -   b. R², R³, and R⁴ are each independently hydrogen, R′, halogen,        CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,        —COOR′, —NR′COR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂,        —CONR′(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′,        O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, or —O(CH₂)₄N(R′)₂;        wherein R², R³, and R⁴ are each optionally substituted with z        occurrences of R⁶, wherein z is 0-5 and R⁶ is ═O, ═NR″, ═S,        halogen, —CN, —NO₂, or Z-R″, wherein Z is a bond or an        optionally substituted C₁-C₆ alkylidene chain, wherein up to two        methylene units of the chain are optionally and independently        replaced by —NR″—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—,        —CONR″—, —NR″CO—, —NR″CO₂—, —SO₂NR″—, —NR″SO₂—, —CONR″NR″—,        —NR″CONR″—, —OCONR″—, —NR″NR″—, —NR″SO₂NR″—, —SO—, —SO₂—, —PO—,        —PO₂—, or —POR″—, and each occurrence of R^(″) is independently        hydrogen or an optionally substituted C₁-C₆ aliphatic group, a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; or two occurrences of R″ are taken        together with the atom(s) to which they are bound to form an        optionally substituted 3-12 membered saturated, partially        unsaturated, or fully unsaturated monocyclic or bicyclic ring        having 0-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur; and    -   c. each occurrence of R⁵ is independently hydrogen, halogen, R′,        CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂, —(CH₂)₂NO₂, CON(R′)₂,        —CH₂CON(R′)₂, —(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′, —(CH₂)₂COOR′,        —SO₂N(R′)₂, —CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′,        —CH₂NR′SO₂R′, —(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂,        —(CH₂)₂NR′CON(R′)₂, —NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂,        —(CH₂)₂NR′SO₂N(R′)₂, —COCOR′, —CH₂COCOR′, —(CH₂)₂COCOR′,        —N(R′)₂, —CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′, —CH₂OR′, —(CH₂)₂OR′,        —NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′; —CH₂NR′COR′, or        —(CH₂)₂NR′COR′, wherein R⁵ is optionally substituted with y        occurrences of R⁷, wherein y is 0-5 and R⁷ is ═O, ═NR″, ═S,        halogen, —CN, —NO₂, or W—R′, wherein W is a bond or an        optionally substituted C₁-C₆ alkylidene chain, wherein up to two        methylene units of the chain are optionally and independently        replaced by —NR″—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—,        —CONR″—, —NR″CO—, —NR″CO₂—, —SO₂NR″—, —NR″SO₂—, —CONR″NR″—,        —NR″CONR″—, —OCONR″—, —NR″NR″—, —NR″SO₂NR″—, —SO—, —SO₂—, —PO—,        —PO₂—, or —POR″—, and and each occurrence of R^(″) is        independently hydrogen or an optionally substituted C₁-C₆        aliphatic group, a 3-8-membered saturated, partially        unsaturated, or fully unsaturated monocyclic ring having 0-3        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or an 8-12 membered saturated, partially unsaturated, or        fully unsaturated bicyclic ring system having 0-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; or two        occurrences of R″ are taken together with the atom(s) to which        they are bound to form an optionally substituted 3-12 membered        saturated, partially unsaturated, or fully unsaturated        monocyclic or bicyclic ring having 0-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur.

In still other embodiments, for compounds of formula I-C:

-   -   a. R¹ is hydrogen, C₁-C₄alkyl, —COR′, —SO₂R′, or —Si(R′)₃;    -   b. R², R³, and R⁴ are each independently Cl, Br, F, —CN, —COOH,        —COOMe, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,        —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂N(Me)₂, or an        optionally substituted group selected from C₁-C₄alkyl,        C₁-C₄alkyloxy, a 3-8-membered saturated, partially unsaturated,        or fully unsaturated monocyclic ring having 0-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or an        8-12 membered saturated, partially unsaturated, or fully        unsaturated bicyclic ring system having 0-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; wherein        R², R³, and R⁴ are each independently and optionally substituted        with z occurrences of R⁶, wherein z is 0, 1, 2, or 3, and each        occurrence of R⁶ is independently hydrogen, R″, —CH₂R″, halogen,        CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″,        —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂,        —CONR″(CH₂)₂N(R″)₂, —CONR(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂,        —O(CH₂)₂OR″, O(CH₂)₃OR″, O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂,        —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂, —NR″CH(CH₂OH)R″,        —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″, —NR″(CH₂)₃R″,        —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″; each occurrence of R⁵ is        independently CN, —CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂,        OR′, —CH₂OR′, —CON(R′)₂, —SO₂N(R′)₂, —N(R′)₂, or R′, wherein R⁵        is optionally substituted y occurrences of R⁷, wherein y is 0,        1, 2, or 3, and each occurrence of R⁷ is independently hydrogen,        R″, —CH₂R″, halogen, CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″,        —CH₂OR″, —SR″, —CH₂SR″, —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂,        —SO₂N(R″)₂, —CONR″(CH₂)₂N(R″)₂, —CONR′(CH₂)₃N(R″)₂,        —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″, O(CH₂)₃OR″, O(CH₂)₄OR″,        —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂, —NR″CH(CH₂OH)R″,        —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″, —NR″(CH₂)₃R″,        —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR″(CH₂)₄OR″.

In other embodiments, for compounds of formula I-C and subsets describeddirectly above, R¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl,n-butyl, p-toluenesulfonyl (Ts), t-butyldimethylsilyl (TBS),triisopropylsilyl (TIPS), or triethylsilyl (TES).

In still other embodiments, for compounds of formula I-C and subsetsdescribed directly above, R², R³, and R⁴ are each hydrogen. In otherembodiments, one of R², R³, or R⁴ is hydrogen. In yet other embodiments,two of R², R³, or R⁴ is hydrogen. In yet other embodiments, R² and R⁴are both hydrogen, and R³ is halogen, CN, NO₂, or V—R′. In still otherembodiments, R² and R⁴ are both hydrogen, and R³ is an optionallysubstituted group selected from a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In yet other embodiments, R² and R⁴ are bothhydrogen, and R³ is an optionally substituted 5- or 6-memberedsaturated, partially unsaturated, or fully unsaturated ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur. Inyet other embodiments, R² and R⁴ are both hydrogen, and R³ is anoptionally substituted ring selected from phenyl, pyridyl, pyrimidinyl,thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl,pyrazinyl, thiadiazolyl, or oxadiazolyl.

In other embodiments, for compounds of formula I-C and subsets describeddirectly above, R², R³, and R⁴ are each independently and optionallysubstituted with z occurrences of R⁶, wherein z is 1, 2, or 3 and eachoccurrence of R⁶ is independently F, Cl, Br, CN, OH, NH₂, —CH₂OH,C₁-C₆alkyl, —O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl),—COO(C₁-C₆alkyl), —NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl),—SO₂(C₁-C₆alkyl), —SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or—S(C₁-C₆alkyl), wherein each of the foregoing phenyl, benzyl, andC₁-C₆alkyl groups is independently and optionally substituted, andwherein each of the foregoing C₁-C₆alkyl groups is linear, branched, orcyclic.

In certain exemplary embodiments, for compounds of formula I-C andsubsets described directly above, x is 1, 2, or 3, and at least oneoccurrence of R⁵ is halogen, CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂,—(CH₂)₂NO₂, —CONH₂, —CON(C₁-C₄alkyl), —SO₂NH₂, —SO₂N(C₁-C₄alkyl), NH₂,—N(C₁-C₄alkyl), —OH, —O(C₁-C₄alkyl), —CH₂OH, —CH₂O(C₁-C₄alkyl), or anoptionally substituted 5- or 6-membered unsaturated ring wherein 0-3ring carbon atoms is optionally replaced by oxygen, sulfur, or nitrogen.In other embodiments, x is 1, 2, or 3, and at least one occurrence of R⁵is —OR′.

In still other embodiments, for compounds of formula I-C and subsetsdescribed directly above, R⁵ is optionally substituted with yoccurrences of R⁷, wherein y is 1, 2, or 3 and each occurrence of R⁷ isindependently F, Cl, Br, CN, OH, NH₂, —CH₂OH, C₁-C₆alkyl,—O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl), —COO(C₁-C₆alkyl),—NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl), —SO₂(C₁-C₆alkyl),—SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or —S(C₁-C₆alkyl), whereineach of the foregoing phenyl, benzyl, and C₁-C₆alkyl groups isindependently and optionally substituted, and wherein each of theforegoing C₁-C₆alkyl groups is linear, branched, or cyclic.

In yet other embodiments, x is 1 and compounds have general formulaI-C-i:

wherein R¹, R², R³, and R⁴ are described generally and in subsets aboveand herein, and R⁵ is halogen, R′, CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂,—(CH₂)₂NO₂, CON(R′)₂, —CH₂CON(R′)₂, —(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′,—(CH₂)₂COOR′, —SO₂N(R′)₂, —CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′,—CH₂NR′SO₂R′, —(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂,—(CH₂)₂NR′CON(R′)₂, —NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂,—(CH₂)₂NR′SO₂N(R′)₂, —COCOR′, —CH₂COCOR′, —(CH₂)₂COCOR′, —N(R′)₂,—CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′, —CH₂OR′, —(CH₂)₂OR′, —NR′COR′,—CH₂NR′COR′, or —(CH₂)₂NR′COR′, and R′ is a C₁-C₆aliphatic group or a3-8-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; ortwo occurrences of R^(′), are taken together with the atom(s) to whichthey are bound to form an optionally substituted 3-12 memberedsaturated, partially unsaturated, or fully unsaturated monocyclic orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein each occurrence of R′ is optionallysubstituted with y occurrences of R⁷. In some embodiments, R⁵ is CN,—CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂,—SO₂N(R′)₂, —N(R′)₂, or R′. In certain embodiments, R′ is hydrogen,C₁-C₆alkyl optionally substituted with 1-3 occurrences of R⁷, or is a5-10-membered monocyclic or bicyclic saturated, partially unsaturated orfully unsaturated ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein the ring is optionallysubstituted with 1-3 occurrences of R⁷. In other embodiments, R′ ishydrogen, C₁-C₄alkyl optionally substituted with 1-3 occurrences of R⁷,or is a ring selected from (i)-(xLvi) or (xLvii) described in [0059].

In yet other embodiments, x is 1 and compounds have general formulaI-C-ii:

wherein R¹, R², R³, and R⁴ are described generally and in subsets aboveand herein, and R⁵ is halogen, R′, CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂,—(CH₂)₂NO₂, CON(R′)₂, —CH₂CON(R′)₂, —(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′,—(CH₂)₂COOR′, —SO₂N(R′)₂, —CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′,—CH₂NR′SO₂R′, —(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂,—(CH₂)₂NR′CON(R′)₂, —NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂,—(CH₂)₂NR′SO₂N(R′)₂, —COCOR′, —CH₂COCOR′, —(CH₂)₂COCOR′, —N(R′)₂,—CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′, —CH₂OR′, —(CH₂)₂OR′, —NR′COR′,—CH₂NR′COR′, or —(CH₂)₂NR′COR′, and R′ is a C₁-C₆aliphatic group or a3-8-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; ortwo occurrences of R′, are taken together with the atom(s) to which theyare bound to form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein each occurrence of R′ is optionally substituted with yoccurrences of R⁷. In some embodiments, R⁵ is CN, —CH₂CN, —(CH₂)₂CN,—NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂, —SO₂N(R′)₂, —N(R′)₂,or R′. In certain embodiments, R′ is hydrogen, C₁-C₆alkyl optionallysubstituted with 1-3 occurrences of R⁷, or is a 5-10-membered monocyclicor bicyclic saturated, partially unsaturated or fully unsaturated ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein the ring is optionally substituted with 1-3 occurrencesof R⁷. In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionallysubstituted with 1-3 occurrences of R⁷, or is a ring selected from(i)-(xLvi) or (xLvii) described in [0059].

In still other embodiments, each occurrence of R⁵ is independently CN,—CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂,—SO₂N(R′)₂, —N(R′)₂, or R′. In still other embodiments, each occurrenceof R⁵ is independently hydrogen, halogen, CN, —CH₂CN, —(CH₂)₂CN, NO₂,—CH₂NO₂, —(CH₂)₂NO₂, —CONH₂, —CON(C₁-C₄alkyl), —SO₂NH₂,—SO₂N(C₁-C₄alkyl), NH₂, —N(C₁-C₄alkyl), —OH, —O(C₁-C₄alkyl), —CH₂OH,—CH₂O(C₁-C₄alkyl), or an optionally substituted 5- or 6-memberedunsaturated ring wherein 0-3 ring carbon atoms is optionally replaced byoxygen, sulfur, or nitrogen, wherein R⁵ is optionally substituted by 0-3occurrences of R⁷.

In yet other embodiments, x is 2 and compounds have general formulaI-C-iii:

wherein R¹, R², R³, and R⁴ are described generally and in subsets aboveand herein, and each occurrence of R⁵ is independently halogen, R′, CN,—CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂, —(CH₂)₂NO₂, CON(R′)₂, —CH₂CON(R′)₂,—(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′, —(CH₂)₂COOR′, —SO₂N(R′)₂,—CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′, —CH₂NR′SO₂R′,—(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂, —(CH₂)₂NR′CON(R′)₂,—NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂, —(CH₂)₂NR′SO₂N(R′)₂—COCOR′, —CH₂COCOR′,—(CH₂)₂COCOR′, —N(R′)₂, —CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′, —CH₂OR′,—(CH₂)₂OR′, —NR′COR′—CH₂NR′COR′, or —(CH₂)₂NR′COR′, and R′ is aC₁-C₆aliphatic group or a 3-8-membered saturated, partially unsaturated,or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R′, are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein each occurrence of R′is optionally substituted with y occurrences of R⁷. In some embodiments,R⁵ is CN, —CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′,—CON(R′)₂, —SO₂N(R′)₂, —N(R′)₂, or R′. In certain embodiments, R′ ishydrogen, C₁-C₆alkyl optionally substituted with 1-3 occurrences of R⁷,or is a 5-10-membered monocyclic or bicyclic saturated, partiallyunsaturated or fully unsaturated ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein thering is optionally substituted with 1-3 occurrences of R⁷. In otherembodiments, R′ is hydrogen, C₁-C₄alkyl optionally substituted with 1-3occurrences of R⁷, or is a ring selected from (i)-(xLvi) or (xLvii)described in [0059].

In still other embodiments, each occurrence of R⁵ is independently CN,—CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂,—SO₂N(R′)₂, —N(R′)₂, or R′. In still other embodiments, each occurrenceof R⁵ is independently hydrogen, halogen, CN, —CH₂CN, —(CH₂)₂CN, NO₂,—CH₂NO₂, —(CH₂)₂NO₂, —CONH₂, —CON(C₁-C₄alkyl), —SO₂NH₂,—SO₂N(C₁-C₄alkyl), NH₂, —N(C₁-C₄alkyl), —OH, —O(C₁-C₄alkyl), —CH₂OH,—CH₂O(C₁-C₄alkyl), or an optionally substituted 5- or 6-memberedunsaturated ring wherein 0-3 ring carbon atoms is optionally replaced byoxygen, sulfur, or nitrogen, wherein R⁵ is optionally substituted by 0-3occurrences of R⁷.

In still other embodiments, R¹, R², R³ and R⁴ are each hydrogen, and xis 1, and compounds of formula I-C-iv are provided:

wherein R⁵ is halogen, R′, CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂,—(CH₂)₂NO₂, CON(R′)₂, —CH₂CON(R′)₂, —(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′,—(CH₂)₂COOR′, —SO₂N(R′)₂, —CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′,—CH₂NR′SO₂R′, —(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂,—(CH₂)₂NR′CON(R′)₂, —NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂,—(CH₂)₂NR′SO₂N(R′)₂, —COCOR′, —CH₂COCOR′, —(CH₂)₂COCOR′, —N(R′)₂,—CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′, —CH₂OR′, —(CH₂)₂OR′, —NR′COR′,—CH₂NR′COR′, or —(CH₂)₂NR′COR′, and R′ is a C₁-C₆aliphatic group or a3-8-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; ortwo occurrences of R′, are taken together with the atom(s) to which theyare bound to form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein each occurrence of R′ is optionally substituted with yoccurrences of R⁷. In some embodiments, R⁵ is CN, —CH₂CN, —(CH₂)₂CN,—NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂, —SO₂N(R′)₂, —N(R′)₂,or R′. In certain embodiments, R′ is hydrogen, C₁-C₆alkyl optionallysubstituted with 1-3 occurrences of R⁷, or is a 5-10-membered monocyclicor bicyclic saturated, partially unsaturated or fully unsaturated ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein the ring is optionally substituted with 1-3 occurrencesof R⁷. In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionallysubstituted with 1-3 occurrences of R⁷, or is a ring selected from(i)-(xLvi) or (xLvii) described in [0059].

In still other embodiments, each occurrence of R⁵ is independently CN,—CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂,—SO₂N(R′)₂, —N(R′)₂, or R′. In still other embodiments, each occurrenceof R⁵ is independently hydrogen, halogen, CN, —CH₂CN, —(CH₂)₂CN, NO₂,—CH₂NO₂, —(CH₂)₂NO₂, —CONH₂, —CON(C₁-C₄alkyl), —SO₂NH₂,—SO₂N(C₁-C₄alkyl), NH₂, —N(C₁-C₄alkyl), —OH, —O(C₁-C₄alkyl), —CH₂OH,—CH₂O(C₁-C₄alkyl), or an optionally substituted 5- or 6-memberedunsaturated ring wherein 0-3 ring carbon atoms is optionally replaced byoxygen, sulfur, or nitrogen, wherein R⁵ is optionally substituted by 0-3occurrences of R⁷.

In yet other embodiments, R¹, R², R³ and R⁴ are each hydrogen, x is 1and compounds have general formula I-C-v:

wherein R⁵ is halogen, R′, CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂,—(CH₂)₂NO₂, CON(R′)₂, —CH₂CON(R′)₂, —(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′,—(CH₂)₂COOR′, —SO₂N(R′)₂, —CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′,—CH₂NR′SO₂R′, —(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂,—(CH₂)₂NR′CON(R′)₂, —NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂,—(CH₂)₂NR′SO₂N(R′)₂, —COCOR′, —CH₂COCOR′, —(CH₂)₂COCOR′, —N(R′)₂,—CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′, —CH₂OR′, —(CH₂)₂OR′, —NR′COR′,—CH₂NR′COR′, or —(CH₂)₂NR′COR′, and R′ is a C₁-C₆aliphatic group or a3-8-membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur; ortwo occurrences of R′, are taken together with the atom(s) to which theyare bound to form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein each occurrence of R′ is optionally substituted with yoccurrences of R⁷. In some embodiments, R⁵ is CN, —CH₂CN, —(CH₂)₂CN,—NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂, —SO₂N(R′)₂, —N(R′)₂,or R′. In certain embodiments, R′ is hydrogen, C₁-C₆alkyl optionallysubstituted with 1-3 occurrences of R⁷, or is a 5-10-membered monocyclicor bicyclic saturated, partially unsaturated or fully unsaturated ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein the ring is optionally substituted with 1-3 occurrencesof R⁷. In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionallysubstituted with 1-3 occurrences of R⁷, or is a ring selected from(i)-(xLvi) or (xLvii) described in [0059].

In still other embodiments, each occurrence of R⁵ is independently CN,—CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂,—SO₂N(R′)₂, —N(R′)₂, or R′. In still other embodiments, each occurrenceof R⁵ is independently hydrogen, halogen, CN, —CH₂CN, —(CH₂)₂CN, NO₂,—CH₂NO₂, —(CH₂)₂NO₂, —CONH₂, —CON(C₁-C₄alkyl), —SO₂NH₂,—SO₂N(C₁-C₄alkyl), NH₂, —N(C₁-C₄alkyl), —OH, —O(C₁-C₄alkyl), —CH₂OH,—CH₂O(C₁-C₄alkyl), or an optionally substituted 5- or 6-memberedunsaturated ring wherein 0-3 ring carbon atoms is optionally replaced byoxygen, sulfur, or nitrogen, wherein R⁵ is optionally substituted by 0-3occurrences of R⁷.

In yet other embodiments, R¹, R², R³ and R⁴ are each hydrogen, x is 2and compounds have general formula I-C-vi:

wherein each occurrence of R⁵ is independently halogen, R′, CN, —CH₂CN,—(CH₂)₂CN, NO₂, —CH₂NO₂, —(CH₂)₂NO₂, CON(R′)₂, —CH₂CON(R′)₂,—(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′, —(CH₂)₂COOR′, —SO₂N(R′)₂,—CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′, —CH₂NR′SO₂R′,—(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂, —(CH₂)₂NR′CON(R′)₂,—NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂, —(CH₂)₂NR′SO₂N(R′)₂, —COCOR′,—CH₂COCOR′, —(CH₂)₂COCOR′, —N(R′)₂, —CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′,—CH₂OR′, —(CH₂)₂OR′, —NR′COR′, —CH₂NR′COR′, or —(CH₂)₂NR′COR′, and R′ isa C₁-C₆aliphatic group or a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R′, are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein each occurrence of R′is optionally substituted with y occurrences of R⁷. In some embodiments,R⁵ is CN, —CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′,—CON(R′)₂, —SO₂N(R′)₂, —N(R′)₂, or R′. In certain embodiments, R′ ishydrogen, C₁-C₆alkyl optionally substituted with 1-3 occurrences of R⁷,or is a 5-10-membered monocyclic or bicyclic saturated, partiallyunsaturated or fully unsaturated ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein thering is optionally substituted with 1-3 occurrences of R⁷. In otherembodiments, R′ is hydrogen, C₁-C₄alkyl optionally substituted with 1-3occurrences of R⁷, or is a ring selected from (i)-(xLvi) or (xLvii)described in [0059].

In still other embodiments, each occurrence of R⁵ is independently CN,—CH₂CN, —(CH₂)₂CN, —NO₂, —CH₂NO₂, —(CH₂)₂NO₂, OR′, —CH₂OR′, —CON(R′)₂,—SO₂N(R′)₂, —N(R′)₂, or R′. In still other embodiments, each occurrenceof R⁵ is independently hydrogen, halogen, CN, —CH₂CN, —(CH₂)₂CN, NO₂,—CH₂NO₂, —(CH₂)₂NO₂, —CONH₂, —CON(C₁-C₄alkyl), —SO₂NH₂,—SO₂N(C₁-C₄alkyl), NH₂, —N(C₁-C₄alkyl), —OH, —O(C₁-C₄alkyl), —CH₂OH,—CH₂O(C₁-C₄alkyl), or an optionally substituted 5- or 6-memberedunsaturated ring wherein 0-3 ring carbon atoms is optionally replaced byoxygen, sulfur, or nitrogen, wherein R⁵ is optionally substituted by 0-3occurrences of R⁷.

Representative examples of compounds of formula I are set forth below inTable 1.

TABLE 1 Examples of Compounds of Formula I:

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

Certain additional subsets of compounds of general formula I include:

Compounds of Formula I-B:

-   -   wherein R¹, R², R³, R⁴, R⁵ and x are each described generally        above and in subsets described above and herein.

In some embodiments, for compounds of formula I-B:

-   -   a. R¹ is:        -   i. T-R′, wherein T is a bond or an optionally substituted            C₁-C₆alkylidene chain wherein up to two methylene units are            optionally and independently replaced with —O—, —S—, —NR′—,            —OCO—, —COO—, —SO₂— or —CO—, and R′ is hydrogen,            C₁-C₄-alkyl, or an optionally substituted 5- or 6-membered            aryl or heteroaryl group, or        -   ii. —Si(R′)₃, wherein R′ is hydrogen, C₁-C₄-alkyl, or an            optionally substituted 5- or 6-membered saturated, partially            unsaturated, or fully unsaturated monocyclic ring having 0-3            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;    -   b. R², R³, and R⁴ are each independently hydrogen, R′, halogen,        CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,        —COOR′, —NR′COR′, —NR′C(O)OR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′,        —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂, —CONR′(CH₂)₃N(R′)₂,        —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′, O(CH₂)₄OR′,        —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, or —O(CH₂)₄N(R′)₂; wherein R²,        R³, and R⁴ are each optionally substituted with z occurrences of        R⁶, wherein z is 0-5 and R⁶ is ═O, ═NR″, ═S, halogen, —CN, —NO₂,        or Z-R″, wherein Z is a bond or an optionally substituted C₁-C₆        alkylidene chain, wherein up to two methylene units of the chain        are optionally and independently replaced by —NR″—, —S—, —O—,        —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO₂—,        —SO₂NR″—, —NR″SO₂—, —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—,        —NR″SO₂NR″—, —SO—, —SO₂—, —PO—, —PO₂—, or —POR″—, and each        occurrence of R^(″) is independently hydrogen or an optionally        substituted C₁-C₆ aliphatic group, a 3-8-membered saturated,        partially unsaturated, or fully unsaturated monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, or an 8-12 membered saturated, partially        unsaturated, or fully unsaturated bicyclic ring system having        0-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or two occurrences of R″ are taken together with the        atom(s) to which they are bound to form an optionally        substituted 3-12 membered saturated, partially unsaturated, or        fully unsaturated monocyclic or bicyclic ring having 0-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur; and    -   c. each occurrence of R⁵ is independently hydrogen, R′, —CH₂R′,        halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′,        —CH₂SR′, —COOR′, —NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′,        —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂,        —CONR(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′,        O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,        —NR′CH₂(CH₃)R′, —NR′(CH₂)₂R′, —NR′(CH₂)₃R′, —NR′(CH₂)₄R′,        —NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —NR′(CH₂)₃N(R′)₂,        —NR′(CH₂)₄N(R′)₂, —NR′(CH₂)OR′, —NR′(CH₂)₂OR′, —NR′(CH₂)₃OR′, or        —NR′(CH₂)₄OR′, wherein R⁵ is optionally substituted with y        occurrences of R⁷, wherein y is 0-5 and R⁷ is ═O, ═NR″, ═S,        halogen, —CN, —NO₂, or W—R′, wherein W is a bond or an        optionally substituted C₁-C₆ alkylidene chain, wherein up to two        methylene units of the chain are optionally and independently        replaced by —NR″—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—,        —CONR″—, —NR″CO—, —NR″CO₂—, —SO₂NR″—, —NR″SO₂—, —CONR″NR″—,        —NR″CONR″—, —OCONR″—, —NR″NR″—, —NR″SO₂NR″—, —SO—, —SO₂—, —PO—,        —PO₂—, or —POR″—, and and each occurrence of R″ is independently        hydrogen or an optionally substituted C₁-C₆ aliphatic group, a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; or two occurrences of R″ are taken        together with the atom(s) to which they are bound to form an        optionally substituted 3-12 membered saturated, partially        unsaturated, or fully unsaturated monocyclic or bicyclic ring        having 0-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur.

In still other embodiments, for compounds of formula I-B:

-   -   a. R¹ is hydrogen, C₁-C₄alkyl, —COR′, —SO₂R′, or —Si(R′)₃;    -   b. R² and R⁴ are each independently Cl, Br, F, —CN, —COOH,        —COOMe, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,        —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂N(Me)₂, or an        optionally substituted group selected from C₁-C₄alkyl,        C₁-C₄alkyloxy, a 3-8-membered saturated, partially unsaturated,        or fully unsaturated monocyclic ring having 0-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or an        8-12 membered saturated, partially unsaturated, or fully        unsaturated bicyclic ring system having 0-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; wherein        R² and R⁴ are each independently and optionally substituted with        z occurrences of R⁶, wherein z is 0, 1, 2, or 3, and each        occurrence of R⁶ is independently hydrogen, R″, —CH₂R″, halogen,        CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″,        —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂,        —CONR″(CH₂)₂N(R″)₂, —CONR′(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂,        —O(CH₂)₂OR″, O(CH₂)₃OR″, O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂,        —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂, —NR″CH(CH₂OH)R″,        —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″, —NR″(CH₂)₃R″,        —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″;    -   c. R³ is independently Cl, Br, F, —CN, —COOH, —COOMe, —NH₂,        —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,        —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂N(Me)₂, or an optionally        substituted group selected from C₁-C₄alkyl, C₁-C₄alkyloxy,        wherein R³ is independently and optionally substituted with z        occurrences of R⁶ wherein z is 0 or 1, and each occurrence of R⁶        is independently hydrogen, R″, —CH₂R″, halogen, CN, NO₂,        —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″, —COOR″,        —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂, —CONR″(CH₂)₂N(R″)₂,        —CONR(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″, O(CH₂)₃OR″,        O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂,        —NR″CH(CH₂OH)R″, —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″,        —NR″(CH₂)₃R″, —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″;    -   d. each occurrence of R⁵ is independently hydrogen, R′, —CH₂R′,        halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′,        —CH₂SR′, —COOR′, —NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′,        —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂,        —CONR(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′,        O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,        —NR′CH₂(CH₃)R′, —NR′(CH₂)₂R′, —NR′(CH₂)₃R′, —NR′(CH₂)₄R′,        —NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —NR′(CH₂)₃N(R′)₂,        —NR′(CH₂)₄N(R′)₂, —NR′(CH₂)OR′, —NR′(CH₂)₂OR′, —NR′(CH₂)₃OR′, or        —NR′(CH₂)₄OR′, wherein R⁵ is optionally substituted with y        occurrences of R⁷, wherein y is 0, 1, 2, or 3, and each        occurrence of R⁷ is independently hydrogen, R″, —CH₂R″, halogen,        CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″,        —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂,        —CONR″(CH₂)₂N(R″)₂, —CONR′(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂,        —O(CH₂)₂OR″, O(CH₂)₃OR″, O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂,        —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂, —NR″CH(CH₂OH)R″,        —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″, —NR″(CH₂)₃R″,        —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR″(CH₂)₄OR″.

In other embodiments, for compounds of formula I-B and subsets describeddirectly above, R¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl,n-butyl, p-toluenesulfonyl (Ts), t-butyldimethylsilyl (TBS),triisopropylsilyl (TIPS), or triethylsilyl (TES).

In still other embodiments, for compounds of formula I-B and subsetsdescribed directly above, R², R³, and R⁴ are each hydrogen. In otherembodiments, one of R², R³, or R⁴ is hydrogen. In yet other embodiments,two of R², R³, or R⁴ is hydrogen. In yet other embodiments, R² and R⁴are both hydrogen, and R³ is halogen, CN, NO₂, or V—R′. In still furtherembodiments, R² and R⁴ are both hydrogen and R³ is halogen. In yetfurther embodiments, R² and R⁴ are both hydrogen and R³ is Cl.

In other embodiments, for compounds of formula I-B and subsets describeddirectly above, R², R³, and R⁴ are each independently and optionallysubstituted with z occurrences of R⁶, wherein z is 1, 2, or 3 and eachoccurrence of R⁶ is independently F, Cl, Br, CN, OH, NH₂, —CH₂OH,C₁-C₆alkyl, —O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl),—COO(C₁-C₆alkyl), —NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl),—SO₂(C₁-C₆alkyl), —SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or—S(C₁-C₆alkyl), wherein each of the foregoing phenyl, benzyl, andC₁-C₆alkyl groups is independently and optionally substituted, andwherein each of the foregoing C₁-C₆alkyl groups is linear, branched, orcyclic with the proviso that R³ is not phenyl.

In certain exemplary embodiments, for compounds of formula I-B andsubsets described directly above, x is 1, 2, or 3, and at least oneoccurrence of R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′,—NR′(CH₂)R′, —NR′CH₂(CH₃)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, or—NR′(CH₂)₂N(R′)₂. In other embodiments, x is 1, 2, or 3, and at leastone occurrence of R⁵ is —OR′. In yet other embodiments, x is 1, 2, or 3,and at least one occurrence of R⁵ is —NR′COR′, —NR′COCH₂R′, or—NR′CO(CH₂)₂R′. In still other embodiments, x is 1, 2, or 3, and atleast one occurrence of R⁵ is an optionally substituted C₁-C₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, for compounds of formula I-B and subsetsdescribed directly above, R⁵ is optionally substituted with yoccurrences of R⁷, wherein y is 1, 2, or 3 and each occurrence of R⁷ isindependently F, Cl, Br, CN, OH, NH₂, —CH₂OH, C₁-C₆alkyl,—O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl), COO(C₁-C₆alkyl),—NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl), —SO₂(C₁-C₆alkyl),—SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or —S(C₁-C₆alkyl), whereineach of the foregoing phenyl, benzyl, and C₁-C₆alkyl groups isindependently and optionally substituted, and wherein each of theforegoing C₁-C₆alkyl groups is linear, branched, or cyclic.

In yet other embodiments, for compounds of formula I-B and subsetsdescribed directly above, x is 1, 2, or 3; at least one occurence of R⁵is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,—NR′CH₂(CH₃)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′,—NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphaticgroup or a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R′, are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein each occurrence of R′is optionally substituted with y occurrences of R⁷. In certainembodiments, R′ is hydrogen, C₁-C₆alkyl optionally substituted with 1-3occurrences of R⁷, or is a 5-10-membered monocyclic or bicyclicsaturated, partially unsaturated or fully unsaturated ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein the ring is optionally substituted with 1-3 occurrences of R⁷.In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionally substitutedwith 1-3 occurrences of R⁷, or is a ring selected from (i)-(xLvi) or(xLvii) described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ andthe two occurrences of R′ are taken together with the nitrogen atom towhich they are bound to form an optionally substituted 3-10-memberedmonocyclic or bicyclic heterocyclic ring. In certain embodiments, thering is selected from (a)-(o) described in [0060].

-   -   wherein y and R⁷ are described generally and in subsets above.

In yet other embodiments, x is 1 and compounds have general formulaI-B-i:

-   -   wherein R¹, R², R³, and R⁴ are described generally and in        subsets above and herein, and R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′,        —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′CH₂(CH₃)R′—NR′(CH₂)₂R′,        NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′,        or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic group or a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; or two occurrences of R′, are taken        together with the atom(s) to which they are bound to form an        optionally substituted 3-12 membered saturated, partially        unsaturated, or fully unsaturated monocyclic or bicyclic ring        having 0-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein each occurrence of R′ is optionally        substituted with y occurrences of R⁷. In some embodiments, R⁵ is        N(R′)₂. In certain embodiments, R′ is hydrogen, C₁-C₆alkyl        optionally substituted with 1-3 occurrences of R⁷, or is a        5-10-membered monocyclic or bicyclic saturated, partially        unsaturated or fully unsaturated ring having 0-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        the ring is optionally substituted with 1-3 occurrences of R⁷.        In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionally        substituted with 1-3 occurrences of R⁷, or is a ring selected        from (i)-(xLvi) or (xLvii) described in [0059]. In yet other        embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are        taken together with the nitrogen atom to which they are bound to        form an optionally substituted 3-10-membered monocyclic or        bicyclic heterocyclic ring. In certain embodiments, the ring is        selected from (a)-(o) described in [0060].

In yet other embodiments, x is 0-3 and compounds have general formulaI-B-ii:

-   -   wherein R¹, R², R³, and R⁴ are described generally and in        subsets above and herein, and each R⁵ is independently selected        from halogen, optionally substituted C₁-C₆ alkyl, —SR′, —CN,        —COOH, —CO₂R′, —CON((R′)₂, —N(R′)₂, —NR′CH(CH₂OH)R′,        —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′CH(CH₃)R′—NR′(CH₂)₂R′,        NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂—OR′, —NR′COR′, —NR′COCH₂R′, or        —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆ aliphatic group or a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; or two occurrences of R′, are taken        together with the atom(s) to which they are bound to form an        optionally substituted 3-12 membered saturated, partially        unsaturated, or fully unsaturated monocyclic or bicyclic ring        having 0-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein each occurrence of R′ is optionally        substituted with y occurrences of R⁷. In some embodiments, R⁵ is        N(R′)₂. In certain embodiments, R′ is hydrogen, C₁-C₆ alkyl        optionally substituted with 1-3 occurrences of R⁷, or is a        5-10-membered monocyclic or bicyclic saturated, partially        unsaturated or fully unsaturated ring having 0-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        the ring is optionally substituted with 1-3 occurrences of R⁷.        In other embodiments, R′ is hydrogen, C₁-C₄ alkyl optionally        substituted with 1-3 occurrences of R⁷, or is a ring selected        from (i)-(xLvi) or (xLvii) described in [0059]. In yet other        embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are        taken together with the nitrogen atom to which they are bound to        form an optionally substituted 3-10-membered monocyclic or        bicyclic heterocyclic ring. In certain embodiments, the ring is        selected from (a)-(o) described in [0060].

In yet other embodiments, x is 1-4 and compounds have general formulaI-B-iii:

-   -   wherein:    -   R³ is an optionally substituted group selected from halogen,        optionally substituted C₁₋₆ alkyl, CN, N(R′)₂, CO₂R′, NR′COR′,        CON(R′)₂, CH₂N(R′)₂, OR′, SR′, CH₂OR′;

-   x is 1, 2, or 3; and at least one occurence of R⁵ is selected from    halogen, optionally substituted C1-C6 aliphatic group, —SR′, —CN,    —COOH, —CO₂R′, —CON((R′)₂, —N(R′)₂, —NR′CH(CH₂OH)R′,    —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′CH(CH₃)R′—NR′(CH₂)₂R′,    NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′, or    —NR′CO(CH₂)₂R′; and R′ is selected from hydrogen, a C₁-C₆aliphatic    group optionally substituted with y occurrences of R⁷, or is a ring    selected from (i)-(xLvi) or (xLvii) described in [0059]. In yet    other embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are    taken together with the nitrogen atom to which they are bound to    form an optionally substituted 3-10-membered monocyclic or bicyclic    heterocyclic ring. In certain embodiments, the ring is selected from    (a)-(o) described in [0060].

In still other embodiments, R¹, R² and R⁴ are each hydrogen, and x is0-3, and compounds of formula I-B-iv are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from halogen,        optionally substituted C1-6 aliphatic, CN, N(R′)₂, CO₂R′,        NR′COR′, CON(R′)₂, CH₂N(R′)₂, OR′, SR′, CH₂OR′;

-   R⁵ is selected from halogen, optionally substituted C1-C6 aliphatic    group, —SR′, —CN, —COOH, —CO₂R′, —CON((R′)₂, —N(R′)₂,    —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,    —NR′CH(CH₃)R′—NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′,    —NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is selected from    hydrogen, a C₁-C₆aliphatic group optionally substituted with y    occurrences of R⁷, or is a ring selected from (i)-(xLvi) or (xLvii)    described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ and the    two occurrences of R′ are taken together with the nitrogen atom to    which they are bound to form an optionally substituted 3-10-membered    monocyclic or bicyclic heterocyclic ring. In certain embodiments,    the ring is selected from (a)-(o) described in [0060].

In still other embodiments, R¹, R² and R⁴ are each hydrogen, and x is 2,and compounds of formula I-B-v are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from halogen,        optionally substituted C₁₋₆ aliphatic, CN, N(R′)₂, CO₂R′,        NR′COR′, CON(R′)₂, CH₂N(R′)₂, OR′, SR′, CH₂OR′;

-   R⁵ is selected from halogen, optionally substituted C₁-C₆ aliphatic    group, —SR′, —CN, —COOH, —CO₂R′, —CON((R′)₂, —N(R′)₂,    —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,    —NR′CH(CH₃)R′—NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′,    —NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is selected from    hydrogen, a C₁-C₆aliphatic group optionally substituted with y    occurrences of R⁷, or is a ring selected from (i)-(xLvi) or (xLvii)    described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ and the    two occurrences of R′ are taken together with the nitrogen atom to    which they are bound to form an optionally substituted 3-10-membered    monocyclic or bicyclic heterocyclic ring. In certain embodiments,    the ring is selected from (a)-(o) described in [0060].

In still other embodiments, R¹, R² and R⁴ are each hydrogen, and x is 2,and compounds of formula I-B-vi are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from halogen,        optionally substituted C₁₋₆ aliphatic, CN, N(R′)₂, CO₂R′,        NR′COR′, CON(R′)₂, CH₂N(R′)₂, OR′, SR′, CH₂OR′;

-   R⁵ is selected from halogen, optionally substituted C1-C6 aliphatic    group, —SR′, —CN, —COOH, —CO₂R′, —CON((R′)₂, —N(R′)₂,    —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,    —NR′CH(CH₃)R′—NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′,    —NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is selected from    hydrogen, a C₁-C₆aliphatic group optionally substituted with y    occurrences of R⁷, or is a ring selected from (i)-(xLvi) or (xLvii)    described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ and the    two occurrences of R′ are taken together with the nitrogen atom to    which they are bound to form an optionally substituted 3-10-membered    monocyclic or bicyclic heterocyclic ring. In certain embodiments,    the ring is selected from (a)-(o) described in [0060].

Certain additional subsets of compounds of general formula I include:

Compounds of Formula I-E:

-   -   wherein R¹, R², R³, R⁴, R⁵ and x are each described generally        above and in subsets described above and herein.

In some embodiments, for compounds of formula I-E:

-   -   a. R¹ is:        -   i. T-R′, wherein T is a bond or an optionally substituted            C₁-C₆alkylidene chain wherein up to two methylene units are            optionally and independently replaced with —O—, —S—, —NR′—,            —OCO—, —COO—, —SO₂— or —CO—, and R′ is hydrogen,            C₁-C₄-alkyl, or an optionally substituted 5- or 6-membered            aryl or heteroaryl group, or        -   ii. —Si(R′)₃, wherein R′ is hydrogen, C₁-C₄-alkyl, or an            optionally substituted 5- or 6-membered saturated, partially            unsaturated, or fully unsaturated monocyclic ring having 0-3            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;    -   b. R², R³, and R⁴ are each independently hydrogen, R′, halogen,        CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,        —COOR′, —NR′COR′, —NR^(o)C(O)OR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′,        —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂, —CONR′(CH₂)₃N(R′)₂,        —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′, O(CH₂)₄OR′,        —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, or —O(CH₂)₄N(R′)₂; wherein R²,        R³, and R⁴ are each optionally substituted with z occurrences of        R⁶, wherein z is 0-5 and R⁶ is ═O, ═NR″, ═S, halogen, —CN, —NO₂,        or Z-R″, wherein Z is a bond or an optionally substituted C₁-C₆        alkylidene chain, wherein up to two methylene units of the chain        are optionally and independently replaced by —NR″—, —S—, —O—,        —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO₂—,        —SO₂NR″—, —NR″SO₂—, —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—,        —NR″SO₂NR″—, —SO—, —SO₂—, —PO—, —PO₂—, or —POR″—, and each        occurrence of R^(″) is independently hydrogen or an optionally        substituted C₁-C₆ aliphatic group, a 3-8-membered saturated,        partially unsaturated, or fully unsaturated monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, or an 8-12 membered saturated, partially        unsaturated, or fully unsaturated bicyclic ring system having        0-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or two occurrences of R″ are taken together with the        atom(s) to which they are bound to form an optionally        substituted 3-12 membered saturated, partially unsaturated, or        fully unsaturated monocyclic or bicyclic ring having 0-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   c. each occurrence of R⁵ is independently hydrogen, R′, —CH₂R′,        halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′,        —CH₂SR′, —COOR′, —NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′,        —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂,        —CONR(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′,        O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, NR′(CH₂)R′, —NR′CH(CH₃)R′,        —NR′(CH₂)₂R′, —NR′(CH₂)₃R′, —NR′(CH₂)₄R′, —NR′(CH₂)N(R′)₂,        —NR′(CH₂)₂N(R′)₂, —NR′(CH₂)₃N(R′)₂, —NR′(CH₂)₄N(R′)₂,        —NR′(CH₂)OR′, —NR′(CH₂)₂OR′, —NR′(CH₂)₃OR′, or —NR′(CH₂)₄OR′,        wherein R⁵ is optionally substituted with y occurrences of R⁷,        wherein y is 0-5 and R⁷ is ═O, ═NR″, ═S, halogen, —CN, —NO₂, or        W—R′, wherein W is a bond or an optionally substituted C₁-C₆        alkylidene chain, wherein up to two methylene units of the chain        are optionally and independently replaced by —NR″—, —S—, —O—,        —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR″—, —NR″CO—, —NR″CO₂—,        —SO₂NR″—, —NR″SO₂—, —CONR″NR″—, —NR″CONR″—, —OCONR″—, —NR″NR″—,        —NR″SO₂NR″—, —SO—, —SO₂—, —PO—, —PO₂—, or —POR″—, and and each        occurrence of R^(″) is independently hydrogen or an optionally        substituted C₁-C₆ aliphatic group, a 3-8-membered saturated,        partially unsaturated, or fully unsaturated monocyclic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, or an 8-12 membered saturated, partially        unsaturated, or fully unsaturated bicyclic ring system having        0-5 heteroatoms independently selected from nitrogen, oxygen, or        sulfur; or two occurrences of R″ are taken together with the        atom(s) to which they are bound to form an optionally        substituted 3-12 membered saturated, partially unsaturated, or        fully unsaturated monocyclic or bicyclic ring having 0-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur.

In still other embodiments, for compounds of formula I-E:

-   -   a. R¹ is hydrogen, C₁-C₄alkyl, —COR′, —SO₂R′, or —Si(R′)₃;    -   b. R² and R⁴ are each independently Cl, Br, F, —CN, —COOH,        —COOMe, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,        —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂N(Me)₂, or an        optionally substituted group selected from C₁-C₄alkyl,        C₁-C₄alkyloxy, a 3-8-membered saturated, partially unsaturated,        or fully unsaturated monocyclic ring having 0-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or an        8-12 membered saturated, partially unsaturated, or fully        unsaturated bicyclic ring system having 0-5 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; wherein        R², R³, and R⁴ are each independently and optionally substituted        with z occurrences of R⁶, wherein z is 0, 1, 2, or 3, and each        occurrence of R⁶ is independently hydrogen, R″, —CH₂R″, halogen,        CN, NO₂, —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″,        —COOR″, —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂,        —CONR″(CH₂)₂N(R″)₂, —CONR′(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂,        —O(CH₂)₂OR″, O(CH₂)₃OR″, O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂,        —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂, —NR″CH(CH₂OH)R″,        —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″, —NR″(CH₂)₃R″,        —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″;    -   c. R³ is independently Cl, Br, F, —CN, —COOH, —COOMe, —NH₂,        —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH,        —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂N(Me)₂, or an optionally        substituted group selected from C₁-C₄alkyl, C₁-C₄alkyloxy,        wherein R³ is independently and optionally substituted with z        occurrences of R⁶ wherein z is 0 or 1, and each occurrence of R⁶        is independently hydrogen, R″, —CH₂R″, halogen, CN, NO₂,        —N(R″)₂, —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″, —COOR″,        —NR″COR″, —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂, —CONR″(CH₂)₂N(R″)₂,        —CONR(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″, O(CH₂)₃OR″,        O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂,        —NR″CH(CH₂OH)R″, —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″,        —NR″(CH₂)₃R″, —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR′(CH₂)₄OR″;    -   d. each occurrence of R⁵ is independently hydrogen, R′, —CH₂R′,        halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′,        —CH₂SR′, —COOR′, —NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′,        —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂,        —CONR(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′,        O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′CH(CH₃)R′,        —NR′(CH₂)₂R′, —NR′(CH₂)₃R′, —NR′(CH₂)₄R′, —NR′(CH₂)N(R′)₂,        —NR′(CH₂)₂N(R′)₂, —NR′(CH₂)₃N(R′)₂, —NR′(CH₂)₄N(R′)₂,        —NR′(CH₂)OR′, —NR′(CH₂)₂OR′, —NR′(CH₂)₃OR′, or —NR′(CH₂)₄OR′,        wherein R⁵ is optionally substituted with y occurrences of R⁷,        wherein y is 0, 1, 2, or 3, and each occurrence of R⁷ is        independently hydrogen, R″, —CH₂R″, halogen, CN, NO₂, —N(R″)₂,        —CH₂N(R″)₂, —OR″, —CH₂OR″, —SR″, —CH₂SR″, —COOR″, —NR″COR″,        —NR″COOR″, —CON(R″)₂, —SO₂N(R″)₂, —CONR″(CH₂)₂N(R″)₂,        —CONR′(CH₂)₃N(R″)₂, —CONR″(CH₂)₄N(R″)₂, —O(CH₂)₂OR″, O(CH₂)₃OR″,        O(CH₂)₄OR″, —O(CH₂)₂N(R″)₂, —O(CH₂)₃N(R″)₂, —O(CH₂)₄N(R″)₂,        —NR″CH(CH₂OH)R″, —NR″CH(CH₂CH₂OH)R″, —NR″(CH₂)R″, —NR″(CH₂)₂R″,        —NR″(CH₂)₃R″, —NR″(CH₂)₄R″, —NR″(CH₂)N(R″)₂, —NR″(CH₂)₂N(R″)₂,        —NR″(CH₂)₃N(R″)₂, —NR″(CH₂)₄N(R″)₂, —NR″(CH₂)OR″, —NR″(CH₂)₂OR″,        —NR″(CH₂)₃OR″, or —NR″(CH₂)₄OR″.

In other embodiments, for compounds of formula I-E and subsets describeddirectly above, R¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl,n-butyl, p-toluenesulfonyl (Ts), t-butyldimethylsilyl (TBS),triisopropylsilyl (TIPS), or triethylsilyl (TES).

In still other embodiments, for compounds of formula I-E and subsetsdescribed directly above, R², R³, and R⁴ are each hydrogen. In otherembodiments, one of R², R³, or R⁴ is hydrogen. In yet other embodiments,two of R², R³, or R⁴ is hydrogen. In yet other embodiments, R² and R⁴are both hydrogen, and R³ is halogen, CN, NO₂, or V—R′. In still furtherembodiments R² and R⁴ are both hydrogen and R³ is halogen. In yetfurther embodiments R² and R⁴ are both hydrogen and R³ is Cl.

In other embodiments, for compounds of formula I-E and subsets describeddirectly above, R², R³, and R⁴ are each independently and optionallysubstituted with z occurrences of R⁶, wherein z is 1, 2, or 3 and eachoccurrence of R⁶ is independently F, Cl, Br, CN, OH, NH₂, —CH₂OH,C₁-C₆alkyl, —O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl),—COO(C₁-C₆alkyl), —NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl),—SO₂(C₁-C₆alkyl), —SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or—S(C₁-C₆alkyl), wherein each of the foregoing phenyl, benzyl, andC₁-C₆alkyl groups is independently and optionally substituted, andwherein each of the foregoing C₁-C₆alkyl groups is linear, branched, orcyclic.

In certain exemplary embodiments, for compounds of formula I-E andsubsets described directly above, x is 1, 2, or 3, and at least oneoccurrence of R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′,—NR′(CH₂)R′, —NR′CH(CH₃)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, or—NR′(CH₂)₂N(R′)₂. In other embodiments, x is 1, 2, or 3, and at leastone occurrence of R⁵ is —OR′. In yet other embodiments, x is 1, 2, or 3,and at least one occurrence of R⁵ is —NR′COR′, —NR′COCH₂R′, or—NR′CO(CH₂)₂R′. In still other embodiments, x is 1, 2, or 3, and atleast one occurrence of R⁵ is an optionally substituted C₁-C₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In still other embodiments, for compounds of formula I-E and subsetsdescribed directly above, R⁵ is optionally substituted with yoccurrences of R⁷, wherein y is 1, 2, or 3 and each occurrence of R⁷ isindependently F, Cl, Br, CN, OH, NH₂, —CH₂OH, C₁-C₆alkyl,—O(C₁-C₆alkyl), —CH₂O(C₁-C₆alkyl), —CO(C₁-C₆alkyl), —COO(C₁-C₆alkyl),—NHSO₂(C₁-C₆alkyl), —SO₂NH₂, —CONH₂, —CON(C₁-C₆alkyl), —SO₂(C₁-C₆alkyl),—SO₂phenyl, phenyl, benzyl, —N(C₁-C₆alkyl)₂, or —S(C₁-C₆alkyl), whereineach of the foregoing phenyl, benzyl, and C₁-C₆alkyl groups isindependently and optionally substituted, and wherein each of theforegoing C₁-C₆alkyl groups is linear, branched, or cyclic.

In yet other embodiments, for compounds of formula I-E and subsetsdescribed directly above, x is 1, 2, or 3; at least one occurence of R⁵is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,—NR′CH(CH₃)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′,—NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphaticgroup or a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R′, are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein each occurrence of R′is optionally substituted with y occurrences of R⁷. In certainembodiments, R′ is hydrogen, C₁-C₆alkyl optionally substituted with 1-3occurrences of R⁷, or is a 5-10-membered monocyclic or bicyclicsaturated, partially unsaturated or fully unsaturated ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein the ring is optionally substituted with 1-3 occurrences of R⁷.In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionally substitutedwith 1-3 occurrences of R⁷, or is a ring selected from (i)-(xLvi) or(xLvii) described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ andthe two occurrences of R′ are taken together with the nitrogen atom towhich they are bound to form an optionally substituted 3-10-memberedmonocyclic or bicyclic heterocyclic ring. In certain embodiments, thering is selected from (a)-(o) described in [0060].

-   -   wherein y and R⁷ are described generally and in subsets above.

In yet other embodiments, x is 1 and compounds have general formulaI-E-i:

-   -   wherein R¹, R², R³, and R⁴ are described generally and in        subsets above and herein, and R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′,        —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′CH₂(CH₃)R′—NR′(CH₂)₂R′,        NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂, —OR′, —NR′COR′, —NR′COCH₂R′,        or —NR′CO(CH₂)₂R′; and R′ is a C₁-C₆aliphatic group or a        3-8-membered saturated, partially unsaturated, or fully        unsaturated monocyclic ring having 0-3 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or an 8-12 membered        saturated, partially unsaturated, or fully unsaturated bicyclic        ring system having 0-5 heteroatoms independently selected from        nitrogen, oxygen, or sulfur; or two occurrences of R′, are taken        together with the atom(s) to which they are bound to form an        optionally substituted 3-12 membered saturated, partially        unsaturated, or fully unsaturated monocyclic or bicyclic ring        having 0-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, wherein each occurrence of R′ is optionally        substituted with y occurrences of R⁷. In some embodiments, R⁵ is        N(R′)₂. In certain embodiments, R′ is hydrogen, C₁-C₆alkyl        optionally substituted with 1-3 occurrences of R⁷, or is a        5-10-membered monocyclic or bicyclic saturated, partially        unsaturated or fully unsaturated ring having 0-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        the ring is optionally substituted with 1-3 occurrences of R⁷.        In other embodiments, R′ is hydrogen, C₁-C₄alkyl optionally        substituted with 1-3 occurrences of R⁷, or is a ring selected        from (i)-(xLvi) or (xLvii) described in [0059]. In yet other        embodiments, R⁵ is —N(R′)₂ and the two occurrences of R′ are        taken together with the nitrogen atom to which they are bound to        form an optionally substituted 3-10-membered monocyclic or        bicyclic heterocyclic ring. In certain embodiments, the ring is        selected from (a)-(o) described in [0060].

In still other embodiments, R¹, R², and R⁴ are each hydrogen, andcompounds of formula I-E-ii are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from halogen,        optionally substituted C1-6 alkyl, CN, N(R′)2, CO2R′, NR′COR′,        CON(R′)2, CH2N(R′)₂, OR′, SR′, CH2OR′;    -   x is 1, 2, or 3; and at least one occurence of R⁵ is —N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,        —NR′CH₂(CH₃)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂,        —OR′, —NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a        C₁-C₆aliphatic group optionally substituted with y occurrences        of R⁷, or is a ring selected from (i)-(xLvi) or (xLvii)        described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ and        the two occurrences of R′ are taken together with the nitrogen        atom to which they are bound to form an optionally substituted        3-10-membered monocyclic or bicyclic heterocyclic ring. In        certain embodiments, the ring is selected from (a)-(o) described        in [0060].

In still other embodiments, R¹, R² and R⁴ are each hydrogen, and x is0-3, and compounds of formula I-E-iii are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from halogen,        optionally substituted C1-6 alkyl, CN, N(R′)₂, CO₂R′, NR′COR′,        CON(R′)₂, CH₂N(R′)₂, OR′, SR′, CH₂OR′;

-   R⁵ is —N(R′)₂, —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,    —NR′CH₂(CH₃)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂,    —OR′, —NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a    C₁-C₆aliphatic group optionally substituted with y occurrences of    R⁷, or is a ring selected from (i)-(xLvi) or (xLvii) described in    [0059]. In yet other embodiments, R⁵ is —N(R′)₂ and the two    occurrences of R′ are taken together with the nitrogen atom to which    they are bound to form an optionally substituted 3-10-membered    monocyclic or bicyclic heterocyclic ring. In certain embodiments,    the ring is selected from (a)-(o) described in [0060].

In still other embodiments, R¹, R² and R⁴ are each hydrogen, and x is 1,and compounds of formula I-E-iv are provided:

-   -   wherein:    -   R³ is an optionally substituted group selected from halogen,        optionally substituted C₁₋₆ alkyl, CN, N(R′)₂, CO₂R′, NR′COR′,        CON(R′)₂, CH₂N(R′)₂, OR′, SR′, CH₂OR′; R⁵ is —N(R′)₂,        —NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′,        —NR′CH₂(CH₃)R′, —NR′(CH₂)₂R′, NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂,        —OR′, —NR′COR′, —NR′COCH₂R′, or —NR′CO(CH₂)₂R′; and R′ is a        C₁-C₆aliphatic group optionally substituted with y occurrences        of R⁷, or is a ring selected from (i)-(xLvi) or (xLvii)        described in [0059]. In yet other embodiments, R⁵ is —N(R′)₂ and        the two occurrences of R′ are taken together with the nitrogen        atom to which they are bound to form an optionally substituted        3-10-membered monocyclic or bicyclic heterocyclic ring. In        certain embodiments, the ring is selected from (a)-(o) described        in [0060].

Representative examples of compounds of formula I are set forth below inTable 2. Compounds of Table 2 may also be represented by II-x, where xis the compound number indicated in Table 2.

TABLE 2 Examples of Compounds of Formula I: Cmpd No. Compound 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

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409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

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468

469

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areinhibitors of protein kinases, and thus the present compounds are usefulfor the treatment of diseases, disorders, and conditions including, butnot limited to a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, psychotic disorders, an autoimmune disorder,a condition associated with organ transplant, an inflammatory disorder,an immunologically mediated disorder, a viral disease, or a bonedisorder. In certain embodiments, the compounds are useful for thetreatment of immune responses such as allergic or type Ihypersensitivity reactions or asthma; autoimmune diseases such astransplant rejection, graft versus host disease, rheumatoid arthritis,amyotrophic lateral sclerosis, and multiple sclerosis; neurodegenerativedisorders such as Familial amyotrophic lateral sclerosis (FALS); andsolid and hematologic malignancies such as leukemias and lymphomas.

These compounds and pharmaceutical compositions thereof are also usefulfor treating or preventing a variety of disorders, including, but notlimited to, heart disease, diabetes, Alzheimer's disease,immunodeficiency disorders, inflammatory diseases, hypertension,allergic diseases, autoimmune diseases, destructive bone disorders suchas osteoporosis, proliferative disorders, infectious diseases,immunologically-mediated diseases, and viral diseases. The compositionsare also useful in methods for preventing cell death and hyperplasia andtherefore may be used to treat or prevent reperfusion/ischemia instroke, heart attacks, and organ hypoxia. The compositions are alsouseful in methods for preventing thrombin-induced platelet aggregation.The compositions are especially useful for disorders such as chronicmyelogenous leukemia (CML), acute myeloid leukemia (AML), acutepromyelocytic leukemia (APL), rheumatoid arthritis, asthma,osteoarthritis, ischemia, cancer (including, but not limited to, ovariancancer, breast cancer and endometrial cancer), liver disease includinghepatic ischemia, heart disease such as myocardial infarction andcongestive heart failure, pathologic immune conditions involving T cellactivation, and neurodegenerative disorders.

Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a JAK-3, ROCK and Aurora.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, a psychotic disorder, an autoimmunedisorder, a condition associated with organ transplant, an inflammatorydisorder, an immunologically mediated disorder, a viral disease, or abone disorder is provided comprising administering an effective amountof a compound, or a pharmaceutically acceptable composition comprising acompound to a subject in need thereof. In certain embodiments of thepresent invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of a proliferative disorder, acardiac disorder, a neurodegenerative disorder, a psychotic disorder, anautoimmune disorder, a condition associated with organ transplant, aninflammatory disorder, an immunologically mediated disorder, a viraldisease, or a bone disorder.

In other aspects, the invention comprises a method for treating orlessening the severity of a variety of disorders, including, but notlimited to, heart disease, diabetes, Alzheimer's disease,immunodeficiency disorders, inflammatory diseases, hypertension,allergic diseases, autoimmune diseases, destructive bone disorders suchas osteoporosis, proliferative disorders, infectious diseases,immunologically-mediated diseases, and viral diseases. In other aspects,the invention comprises methods for preventing cell death andhyperplasia and therefore may be used to treat or preventreperfusion/ischemia in stroke, heart attacks, and organ hypoxia. Inother embodiments, the invention comprises methods for preventingthrombin-induced platelet aggregation. The invention also comprisesmethods for treating, lessening the severity or preventing disorderssuch as chronic myelogenous leukemia (CML), acute myeloid leukemia(AML), acute promyelocytic leukemia (APL), rheumatoid arthritis, asthma,osteoarthritis, ischemia, cancer (including, but not limited to, ovariancancer, breast cancer and endometrial cancer), liver disease includinghepatic ischemia, heart disease such as myocardial infarction andcongestive heart failure, pathologic immune conditions involving T cellactivation, and neurodegenerative disorders.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of aproliferative disorder, a cardiac disorder, a neurodegenerativedisorder, an autoimmune disorder, a condition associated with organtransplant, an inflammatory disorder, an immunologically mediateddisorder, a viral disease, or a bone disorder. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “patient”, as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of protein kinases. In one embodiment, the compounds andcompositions of the invention are inhibitors of one or more of JAK-3,ROCK and Aurora isoforms, and thus, without wishing to be bound by anyparticular theory, the compounds and compositions are particularlyuseful for treating or lessening the severity of a disease, condition,or disorder where activation of JAK-3, ROCK or Aurora is implicated inthe disease, condition, or disorder. When activation of JAK-3, ROCK orAurora is implicated in a particular disease, condition, or disorder,the disease, condition, or disorder may also be referred to as a“JAK-3-mediated disease”, “ROCK-mediated disease”, “Aurora-mediateddisease” or disease symptom. Accordingly, in another aspect, the presentinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or one or more ofJAK-3, ROCK or Aurora isoforms is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofJAK-3, ROCK or Aurora may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine inhibition of eitherthe phosphorylation activity or ATPase activity of activated JAK-3, ROCKor Aurora. Alternate in vitro assays quantitate the ability of theinhibitor to bind to JAK-3, ROCK or Aurora. Inhibitor binding may bemeasured by radiolabelling the inhibitor prior to binding, isolating theinhibitor/JAK-3, inhibitor/ROCK or inhibitor/Aurora complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with JAK-3, ROCK or Aurora bound to knownradioligands.

The term “measurably inhibit”, as used herein means a measurable changein JAK-3, ROCK or Aurora activity between a sample comprising saidcomposition and a JAK-3, ROCK or Aurora kinase and an equivalent samplecomprising JAK-3, ROCK or Aurora kinase in the absence of saidcomposition.

The term “JAK-mediated disease”, as used herein means any disease orother deleterious condition in which a JAK family kinase is known toplay a role. Such conditions include, without limitation, immuneresponses such as allergic or type I hypersensitivity reactions, asthma,autoimmune diseases such as transplant rejection, graft versus hostdisease, rheumatoid arthritis, amyotrophic lateral sclerosis, andmultiple sclerosis, neurodegenerative disorders such as Familialamyotrophic lateral sclerosis (FALS), as well as in solid andhematologic malignancies such as leukemias and lymphomas.

The term “ROCK-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition in which ROCK is known toplay a role. The term “ROCK-mediated condition” or “disease” also meansthose diseases or conditions that are alleviated by treatment with aROCK inhibitor. Such conditions include, without limitation,hypertension, angina pectoris, cerebrovascular contraction, asthma,peripheral circulation disorder, premature birth, cancer, erectiledysfunction, arteriosclerosis, spasm (cerebral vasospasm and coronaryvasospasm), retinopathy (e.g., glaucoma), inflammatory disorders,autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy,ischemia/reperfusion-induced injury, and endothelial dysfunction.

The term “Aurora-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition in which Aurora is known toplay a role. The term “Aurora-mediated condition” or “disease” alsomeans those diseases or conditions that are alleviated by treatment witha Aurora inhibitor. Such conditions include, without limitation, immuneresponses such as allergic or type I hypersensitivity reactions, asthma,autoimmune diseases such as transplant rejection, graft versus hostdisease, rheumatoid arthritis, amyotrophic lateral sclerosis, andmultiple sclerosis, neurodegenerative disorders such as Familialamyotrophic lateral sclerosis (FALS), as well as in solid andhematologic malignancies such as leukemias and lymphomas.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

Examples of agents the inhibitors of this invention may also be combinedwith include, without limitation: treatments for Alzheimer's Diseasesuch as Aricept® and Excelon®; treatments for Parkinson's Disease suchas L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine,pergolide, trihexephendyl, and amantadine; agents for treating MultipleSclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®),Copaxone®, and mitoxantrone; treatments for asthma such as albuterol andSingulair®; agents for treating schizophrenia such as zyprexa,risperdal, seroquel, and haloperidol; anti-inflammatory agents such ascorticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; immunomodulatory and immunosuppressive agents such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating implantable medical devices, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device.

Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a kinase inhibitor. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting JAK-3, ROCK orAurora activity in a biological sample or a patient, which methodcomprises administering to the patient, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of JAK-3, ROCK or Aurora kinase activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, blood transfusion, organ-transplantation, biological specimenstorage, and biological assays.

EXAMPLES

Although certain exemplary embodiments are described in detail below, itwill be appreciated that additional compounds of general formula I canbe prepared according to the methods described generally herein usingappropriate starting materials by methods generally available to one ofordinary skill in the art.

3-Bromo-1H-pyrrolo[2,3-b]pyridine (2)

Azaindole 1 (4 g, 0.025 mol) in 100 mL of chloroform was cooled to 0° C.Bromine in 20 mL of chloroform was added dropwise the resulting mixturewas stirred at 0° C. for 1 h. The resulting suspension was diluted with0.5N HCl and the aqueous layer was made basic with 0.5 N NaOH and thesolid filtered to provide 4 g (82%) of crude product 2 that was useddirectly for the next step.

3-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (3)

3 g (0.015 mol) of 2 in 20 mL of anhydrous THF was cooled to −78° C. andn-BuLi 2.5 M in hexanes (6.7 mL, 0.167 mol) was added dropwise. After 15minutes of stirring, tosyl chloride in 5 mL of THF was added dropwise.The cooling bath was removed and the reaction mixture stirred at rt for1 h. Extracted with ether and the organic phase washed with brine, driedwith magnesium sulfate and concentrated in vacuo to give a white solidthat was passed through a pad of silica (70% EtOAc; 30% Hexanes) to give4.65 g (84%) of 3. ¹H NMR CDCl₃ 8.4 (s, 1H), 8.1 (d, 2H), 7.8 (s, 2H),7.2 (m, 3H), 2.3 (s, 3H).

3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(4)

3 (850 mg, 0.0024 mol) was dissolved in 20 mL of DME and pinnacol borane(921 mg, 0.0036 mol), Pd₂Cl₂ (dppf)₂ (197 mg, 0.24 mmol) and KOAc (713mg, 0.00726 mol) were added and the mixture was stirred and refluxed at90° C. for 18 h. Diluted with ethyl acetate and the organic phase washedwith water and brine then dried (Na₂SO₄) and concentrated in vacuo. Theresidue was subjected to flash chromatography (20% EtOAc/80% hexanes) togive 900 mg (99%) of the desired product 4.

3-(2-Methylsulfanyl-pyrimidin-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3b]pyridine(5)

A mixture of boronic ester 4 (900 mg, 0.0023 mol), 4-chloro-2-thiomethylpyrimidine (341 mg, 0.0029 mol), Pd(Ph₃P)₄ (260 mg, 0.23 mmol) and 2 Msodium carbonate (3.4 mL, 0.0068 mol) in 20 mL of DME was refluxed undernitrogen for 18 h. Diluted with ethyl acetate and the organic phasewashed with water and brine then dried (Na₂SO₄) and concentrated invacuo. The residue was subjected to flash chromatography (40% EtOAc/60%hexanes) to give 460 mg (51%) of the desired product 5. ¹H NMR CDCl₃ 8.8(d, 1H), 8.7 (m, 2H), 8.4 (s, 1H), 8.1 (d, 2H), 7.2 (m, 4H), 2.6 (s,3H), 2.3 (s, 3H).

3-(2-Methanesulfonyl-pyrimidin-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(6)

Pyrimidine 5 (460 mg, 0.0012 mol) was dissolved in 20 mL ofmethanol-water (1:1) then oxone (2.14 g, 0.0035 mol) was added and thereaction was refluxed for 18 h. The methanol was removed in vacuo andthe aqueous was extracted with ethyl acetate. The organic phase washedwith water and brine then dried (Na₂SO₄) and concentrated in vacuo. Theresidue was subjected to flash chromatography (40% EtOAc/60% hexanes) togive 160 mg (32%) of the desired product 6. LCMS ES⁺=428.9.

Benzyl-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine (7)

A solution of 6 (20 mg, 0.047 mmol) and benzylamine (0.007 mL, 0.061mmol) in 1 mL of ethanol was heated in a seal tube at 80° C. for 18 h.The solvent was evaporated and the crude product was purified bypreparative TLC (50% EtOAc/50% hexanes) to give 20 mg of product whichwas deprotected with 2 mL of 3N NaOH in methanol for 4 h. Added 2 mL of3N HCl and evaporated to dryness. Reverse phase HPLC (20-70% MeCN-waterwith 0.1% TFA (20 mL/min) gave 10 mg (75%) of 7. ¹H NMR DMSOD₆ 8.7 (s,1H), 8.4 (s, 1H), 8.25 (d, 1H), 8.1 (d, 1H), 7.4 (m, 2H), 7.25 (m, 3H),7.2 (s, 1H), 7.15 (dd, 1H), 7.1 (s, 1H), 4.8 (s, 2H). LCMS ES⁺=302.0.

3-(6-Chloro-pyrimidin-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(8)

A solution of boronate 4 (0.11 g, 0.276 mmol), 4,6-dichloropyrimidine(0.049 g, 0.331 mmol), catalytic Pd(PPh₃)₄ and excess potassiumcarbonate in DMF was heated in the microwave at 160° C. for 5 minutesresulting in conversion to product by TLC (20% EtOAc:hexanes). Thereaction was partitioned between EtOAc/H₂O, extracted, stripped down invacuo and purified by silica column (eluent:5% EtOAc:hexanes) giving 8(0.035 g) as a white solid in 33% yield.

1-{4-[6-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-4-yl]-[1,4]diazepan-1-yl}-ethanone(9)

A solution of 8 (0.035 g, 0.091 mmol), N-acetyl-homopiperizine (0.025 g,0.181 mmol), excess potassium carbonate in DMF was heated at 80° C.resulting in a color change after 5 minutes. LC/MS and TLC indicatedconversion to tosyl protected product after 15 minutes. 1 ml of 6N NaOHand 1 ml of methanol were added to the reaction resulting in theimmediate removal the tosyl group by LC/MS (M+1=337). The reaction waspartitioned between EtOAc/H₂O and extracted. The crude product waspurified by preparative HPLC giving 9 (0.022 g) as a clear oil in 73%yield.

NMR: MeOD 2.0 bs(2H), 2.1 s(3H), 3.6 m(2H), 3.8-4.3 bm(6H), 7.1 d(1H),7.3 m(1H), 8.2 d(1H), 8.35 m(2H), 8.65 d(1H). LC/MS(M+1)=337

Benzyl-(2-chloro-pyrimidin-4-yl)-amine (10)

To a solution of 2,4-dichloropyrimidine (0.15 g, 1.0 mmol), benzylamine(0.109 ml, 1.0 mmol) in THF was added DIPEA (0.526 ml, 3.0 mmol) and thereaction was heated at reflux for 2 hours resulting in formation of a4:1 mixture of regioisomers (desired versus undesired) by TLC (5%Methanol:methylene chloride). The reaction was stripped down in vacuoand purified by silica column (eluent: 2% methanol:methylene chloride)giving 0.12 g (0.548 mmol) of desired product 10 in 54% yield.LC/MS(M+1)=220

Benzyl-(6-chloro-pyrimidin-4-yl)-amine (12)

Benzyl amine (0.697 ml, 6.76 mmol) was added to 4,6-dichloropyrimidine(1.0 g, 6.76 mmol) neat causing a vigorous reaction and color change.The reaction was slowly diluted with methylene chloride resulting in awhite precipitate. 1 ml of triethyl amine was added and TLC indicatedconversion to product (5% MeOH:methylene chloride). The reaction wasloaded directly onto a silica and purified (eluent:2% MeOH:methylenechloride) giving 1.17 g (5.32 mmol) of 12 as a yellow wax in 79% yield.

Benzyl-[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-4-yl]-amine (11)

A solution of 4 (0.36 g, 0.09 mmol), 10 (0.028 g, 0.108 mmol), 2.0MNa₂CO₃ (0.108 ml, 0.271 mmol) and catalytic PdCl₂(PPh₃)₂ in 1 ml of DMSOwas heated in the microwave at 160° C. for 5 minutes resulting inconversion to tosyl protected product by LC/MS(M+1)=456. NaOtBu (0.026g, 0.271 mmol) was added to the reaction and it was heated in themicrowave for 5 minutes at 160° C. resulting in complete conversion toproduct 11. The reaction was filtered and purified by preparative HPLCgiving 0.0032 g of 11 as a white solid in 11% yield.

NMR: MeOD 4.95 bs(2H), 6.6 d(1H), 7.2 m(1H), 7.3-7.5 mm(5H), 8.0 d(1H),8.3 d(1H), 8.4 s(1H), 8.55 d(1H). LC/MS(M+1)=302

Final product 13 was formed as described for 11 giving 0.012 g (0.039mmol) of 13 as a white solid. NMR: MeOD 4.8 s(2H), 7.05 s(1H), 7.2-7.6m(6H), 8.2 s(1H), 8.4 m(2H), 8.55 s(1H). LC/MS(M+1)=302

3-(2-Chloro-pyridin-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(14)

A mixture of azaindole 3 (80 mg, 0.23 mmol), 2-chloropyridine-4-boronicacid (41 mg, 0.27 mmol), Pd(Ph₃P)₄ (20 mg, 0.11 mmol) and 2 M sodiumcarbonate (0.34 mL, 0.68 mmol) in 2 mL of DME was microwaved on high at160° C. for under nitrogen for 15 minutes. Diluted with ethyl acetateand the organic phase washed with water and brine then dried (Na₂SO₄)and concentrated in vacuo. The residue was subjected to flashchromatography (40% EtOAc/60% hexanes) to give 60 mg (68%) of thedesired product 14. ¹H NMR CDCl₃ 8.6 (d, 2H), 8.1 (m, 4H), 7.25 (m, 5H),2.5 (s, 3H). The 2-chloropyridine could be displaced, for example, withbenzylamine in a microwave reaction at 250° C. for 30 min followed bydeprotection to give compound 15.

1-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (16)

7-Azaindole 13 (2.16 g, 0.011 mol) was dissolved in 75 mL of dry DCM.Aluminium trichloride (4.36 g, 0.0327 mol) was added to the solution andthe reaction mixture was stirred for 1 h at rt. Acetyl chloride (1.16mL, 0.0164 mol) was adde dropwise to the mixture and stirred at rt for18 h. 20 mL of methanol was added and the reaction for 1 h. Concentratedin vacuo and suspended in water-EtOAc mixture. Extraction with EtOAc anddrying of the organic gave, after concentration in vacuo, 2.37 g (91%)of compound 14. ¹H NMR CDCl₃ 9.5 (bs, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 7.9(s, 1H), 2.4 (s, 3H).

1-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-3-dimethylamino-propenone(17)

To a suspension of NaH (263 mg, 0.0104 mol) in dry THF at 0° C. wasslowly added 16 (2.37 g, 0.01 mol) in THF. Stirred for 0° C. for 15 minthen p-toluensulfonyl chloride (2.27 g, 0.012 mol) in THF was added andthe reaction miture stirred for 18 h at rt. Quenched with water andextracted with ethyl acetate. The organic layer was dried andconcentrated in vacuo to 3.37 g of a solid residue that was useddirectly for the next step. The above intermediate was mixed withDMF-DMA (5.7 mL, 0.0428 mol) and heated at 100° C. for 22 h.Concentrated in vacuo and subjected to flash chromatography (60%EtOAc/40% hexanes) to give 3.37 g (76% from 17) of the desired product15. ¹H NMR CDCl₃ 8.8 (s, 1H), 8.3 (s, 1H), 8.1 (s, 1H), 8.05 (d, 2H),7.8 (d, 1H), 7.2 (s, 2H), 5.7 (d, 1H), 3.0 (bs, 6H), 2.2 (s, 3H).

6-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidine-2-thione (18)

To a freshly prepared solution of sodium (175 mg, 0.0076 mol) in ethanol(18 mL) were consecutively added compound 17 (1.0 g, 0.0022 mol) andthiourea (187 mg, 0.0025 mol). The mixture was heated to reflux for 4 h.The solvent was removed and the residue was dissolved in 8 mL of water.The solution was neutralized with 1 n HCl and extracted with ethylacetate. The organic phase was dried and concentrated in vacuo toprovide 570 mg (75%) of technically clean 18. ¹H NMR CDCl₃ 12.2 (s, 1H),8.6 (s, 1H), 8.3 (s, 1H), 8.2 (s, 1H), 7.6 (d, 1H), 5.8 (d, 1H).

5-Bromo-3-(2-methylsulfanyl-pyrimidin-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(19)

A suspension of 18 (565 mg, 0.0018 mol), sodium acetate (526 mg, 0.0039mol), methyl iodide (0.126 mL, 0.0020 mol) in 15 mL of ethanol-THF (9:1)was heated to reflux for 2 h. Cooled to rt and filtered. Chromatography(70% EtOAc-30% hexane) provided 48 mg (9%) of the thiomethylintermediate. Tosylation provided 49 mg (70%) of the desired compound19. ¹H NMR CDCl₃ 8.8 (d, 1H), 8.5 (m, 2H), 8.35 (s, 1H), 8.1 (d, 2H),7.25 (m, 3H), 2.7 (s, 3H), 2.3 (s, 3H).

Benzyl-[4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-pyrimidin-2-yl]-amine(20)

This compound could be prepared from 19 via oxone oxidation andbenzylamine displacement following Scheme 1.

5-Bromo-1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (19)

To a suspension of NaH (200 mg, 0.0078 mol) in 15 mL of dry DMF at 0° C.was added azaindole 13 (1.36 g, 0.007 mol) in 5 mL of DMF. Stirred at 0°C. for 10 min. and TBDMSCl in 3 mL of DMF was added and the resultingmixture stirred O.N. Taken in EtOAc and washed with water, brine. Theorganic layer was dried and concentrated in vacuo to an oil that wasused directly for the next step without further purification. ¹H NMRCDCl₃ 8.3 (d, 1H), 7.9 (d, 1H), 7.2 (d, 1H), 6.4 (d, 1H), 0.85 (s, (H),0.5 (s, 6H).

1-(tert-Butyl-dimethyl-silanyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine(20)

To a solution of 19 (1.77 g, 0.0057 mol), 3-diethylpyridyl borane (1.0g, 0.0068 mol) in 80 mL of DME, was added PdCl₂(Ph₃P)₂ (320 mg, 0.455mmol) and aqueous 2M sodium carbonate (8.5 mL, 0.017 mol) undernitrogen. The reaction mixture was refluxed for 3 h. Cooled to rt anddiluted with ethyl acetate and washed with brine. The organic layer wasdried and concentrated to an oil that was subjected to flashchromatography (30% EtOAc-70% hexanes) to give 1 g (57%) of the desiredmaterial 20. ¹H NMR CDCl₃ 8.9 (s, 1H), 8.5 (d, 1H), 8.4 (d, 1H), 8.0 (d,1H), 7.9 (d, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 6.5 (d, 1H), 0.85 (s, 9H),0.55 (s, 6H).

3-Bromo-1-(tert-butyl-dimethyl-silanyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine(21)

A solution of bromine (0.166 mL, 0.0032 mol) in 1 mL of CCl₄ was addeddropwise to a stirred solution of 20 (1.0 g, 0.0032 mol) and pyridine(0.314 mL, 0.0039 mol) in dry CHCl₃ (30 mL) at 0° C. The reactionmixture was stirred at 0° C. for 1 h and then neutralized with 10 mL ofa mixture of sodium bicarbonate-sodium thiosulfate (1:1). The organiclayer was separated and further extracted with dichloromethane (3×10 mL)and the combined organics dried and concentrated in vacuo. The residuewas subjected to flash chromatography (30% EtOAc-70% hexanes) to give0.97 g (78%) of the desired material 21. ¹H NMR CDCl₃ 8.9 (s, 1H), 8.55(d, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.4 (dd, 1H), 7.2 (s,1H), 0.9 (s, 9H), 0.5 (s, 6H).

5-Pyridin-3-yl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(22)

Compound 21 could be desilylated with, for example, 10% HCl andtosylated with, for example, NaH and p-toluenesulfonyl chloride.Compound 22 could be prepared using the same protocol as for compound 4in Scheme 1.

3-(2-Methanesulfonyl-pyrimidin-4-yl)-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(24)

Compound 24 could be prepared using the same protocol as for compound 6in Scheme 1.

3-(6-Chloro-pyrimidin-4-yl)-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(25)

Compound 25 could be prepared using the same protocol as for compound 8in Scheme 1.

3-(2-Chloro-pyridin-4-yl)-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(26)

Compound 26 could be prepared using the same protocol as for compound 14in Scheme 2.

2-Methoxy-4-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzonitrile(29)

In a tube was placed boronic acid 28 (35.4 mg, 200 μmol), and tosylprotected azaindole 3 (65.5 mg, 194 μmol), with sodium carbonate (61.8mg, 583 μmol) and tetrakis(triphenylphosphine)palladium(0) (8.3 mg, 7.2μmol). Water (323 mg) and Ethylene glycol dimethyl ether (848 mg) wereadded and the mixture was deoxygenated. The tube was sealed and heatedto 160 C for 10 minutes with magnetic stirring, utilizing microwaveirradiation. The crude product was extracted with ethyl acetate andwater. The organics were washed with brine, dried over sodium sulfate,filtered and concentrated to give crude product (83 mg). The crude waspurified via flash chromatography and eluted with a gradient from 1:1ethyl acetate/hexane to 100% ethyl acetate to 4/4/1 ethylacetate/hexane/7N ammonia in methanol to give 29 (42 mg, 54%) and 30(7.7 mg, 15%).

2-Methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-benzonitrile (30)

The tosyl protecting group was removed from 29 by refluxing in dioxane(5 ml) with 1N sodium hydroxide (200 μl, 2 eq.) for 4.5 hours. Thereaction was concentrated and extracted with ethyl acetate and saturatedaqueous sodium bicarbonate. The organics were washed with brine, driedover sodium sulfate, filtered and concentrated to give 30 (30 mg, 100%).¹H NMR CD₃CN 10.00 (s, 1H), 8.32 (m, 2H), 7.83 (s, 1H), 7.65 (d, 1H),7.40 (m, 2H), 7.20 (dd, 1H), 4.02 (s, 3H). LC/MS(M+1)=250

2-Methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-benzamide (31)

The nitrile 30 (10 mg, 40 μmol) was dissolved in dimethyl sulfoxide (0.5ml). To this was added potassium carbonate (20 mg) and 30% hydrogenperoxide in water (100 μl). The reaction was warmed to approximately 60C for 15 minutes. The reaction was concentrated to dryness andtriturated in water. The resulting precipitate was filtered and driedin-vacuo overnight to give 31 (10 mg, 93%). ¹H NMR DMSO-d6 11.99 (s,1H), 8.32 (d, 1H), 8.24 (m, 1H), 8.01 (m, 1H), 7.88 (d, 1H), 7.59 (s,1H), 7.40 (s, 1H), 7.37 (m, 2H), 7.15 (dd, 1H), 4.00 (s, 3H).LC/MS(M+1)=268.

Boronic acids 32B through 32F (500 μmol) were placed in tubes withazaindole 3 (87 mg, 250 μmol). In each vial was placed sodium carbonate(53 mg, 500 μmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg,13 μmol). Water (1 ml) and Ethylene glycol dimethyl ether (2 ml) wereadded and the tubes were deoxygenated and sealed. The tubes were heatedto 140 C via microwave, for 10 minutes. The reactions were cooled to 0 Cand quenched with 2N hydrochloric acid in water (1 ml). The reactionswere extracted with ethyl acetate. The organics were washed with brine,dried over sodium sulfate, filtered and concentrated. The products werepurified on silica (50% ethyl acetate/hexane to 100% ethyl acetategradient) to give 33B to 33F.

The compounds 33B to 33F were dissolved in methanol (20 ml) and treatedwith 2N sodium hydroxide in water (1 ml) at room temperature, overnight.The reactions were neutralized with 2N hydrochloric acid (1 ml) andconcentrated to dryness. The products were purified via chromatographyon silica gel (50% ethyl acetate/hexane to 100% ethyl acetate gradient)or mass directed reverse phase chromatography on C18 (15%acetonitrile/water with 0.09% trifluoroacetic acid to 35%acetonitrile/water with 0.09% trifluoroacetic acid over 15 minutes) togive products 34B to 34F.

3-(3-Benzyloxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (34B)

¹H NMR DMSO-d6 11.95 (s, 1H), 8.29 (m, 1H), 8.20 (d, 1H), 7.89 (s, 1H),7.49 (d, 2H), 7.41 (t, 2H), 7.34 (m, 2H), 7.29 (m, 2H), 7.13 (dd, 1H),6.90 (m, 1H), 5.20 (s, 2H). LC/MS(M+1)=301.

3-(4-Benzyloxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (34C)

¹H NMR DMSO-d6 11.84 (s, 1H), 8.28 (m, 2H), 7.76 (s, 1H), 7.61 (d, 2H),7.48 (d, 2H), 7.39 (t, 2H), 7.32 (t, 1H), 7.15 (dd, 1H), 7.09 (d, 2H),5.13 (s, 2H). LC/MS(M+1)=301.

3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (34D)

¹H NMR DMSO-d_(6 11.90) (s, 1H), 8.31 (d, 1H), 8.28 (d, 1H), 7.80 (s,1H), 7.21 (m, 2H), 7.19 (dd, 1H), 7.02 (d, 1H), 3.86 (s, 3H), 3.78 (s,3H). LC/MS(M+1)=255.

3-(3,4,5-Trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (34E)

¹H NMR DMSO-d6 11.85 (s, 1H), 8.29 (d, 1H), 8.27 (d, 1H), 7.83 (s, 1H),7.15 (d, 1H), 6.92 (s, 2H), 3.86 (s, 6H), 3.69 (s, 3H). LC/MS(M+1)=285.

2-Methoxy-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-phenol (34F)

¹H NMR DMSO-d6/D₂O 8.25-8.30 (m, 2H), 7.74 (s, 1H), 7.20 (d, 1H), 7.17(dd, 1H), 7.10 (dd, 1H), 6.86 (d, 1H), 3.88 (s, 3H). LC/MS(M+1)=241.

2-Methoxy-5-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzaldehyde(36)

In a tube was placed boronate ester 35 (131 mg, 500 μmol), and 3 (175mg, 500 μmol), with sodium carbonate (114 mg, 1.08 mmol) andtetrakis(triphenylphosphine)palladium(0) (22 mg, 19 μmol). Water (0.9 g)and Ethylene glycol dimethyl ether (2.1 g) were added and the mixturewas deoxygenated. The tube was sealed and heated to 110 C overnight,with magnetic stirring. The crude product was extracted with ethylacetate and water. The organics were washed with brine, dried oversodium sulfate, filtered and concentrated to give crude product. Thecrude was purified via flash chromatography and eluted with a gradientfrom 1:1 ethyl acetate/hexane to 100% ethyl acetate to 4/4/1 ethylacetate/hexane/7N ammonia in methanol to give 36 (98 mg, 48%).

2-Methoxy-5-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzonitrile(37)

The aldehyde 36 (98 mg, 241 μmol) was dissolved in tetrahydrofuran (5ml). To this was added 30% aqueous ammonium hydroxide (3 ml) and iodine(79 mg, 313 μmol). The reaction was stirred at room temperatureovernight. The reaction was diluted with water and extracted with etherand ethyl acetate. The organics were washed with aqueous sodium sulfite(50 mg) in water (10 ml). The organics were washed with brine, driedover sodium sulfate, filtered and concentrated to give 37 (95.8 mg,98%).

2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-benzonitrile (38)

The nitrile 37 (95.8 mg, 237 μmol) was dissolved in dioxane (5 ml) andtreated with 2N sodium hydroxide in water (250 μl, 500 μmol). Thereaction was sealed and heated to reflux for 2 hours. The reaction wasconcentrated to dryness and extracted with ethyl acetate and water. Theorganics were washed with brine, dried over sodium sulfate, filtered andconcentrated to give crude product (72.3 mg). The crude was purified viaflash chromatography and eluted with a gradient from 1:1 ethylacetate/hexane to 100% ethyl acetate to 4/4/1 ethyl acetate/hexane/7Nammonia in methanol to give 38 (26.7 mg, 45%).

2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-benzamide (39)

The de-tosylated nitrile 38 (26.7 mg, 107 μmol) was dissolved indimethyl sulfoxide (2.49 g). To this was added potassium carbonate (32.7mg, 237 μmol) and 30% hydrogen peroxide in water (85.5 mg) and thereaction was stirred at room temperature overnight. The reaction wasdiluted with water and the resulting precipitate was washed with water,acetonitrile and ether to give final product 39 (25.3 mg, 88%). ¹H NMRDMSO-d6 11.86 (s, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 8.11 (m, 1H), 7.81(m, 2H), 7.70 (s, 1H), 7.55 (s, 1H), 7.21 (d, 1H), 7.16 (m, 1H), 3.91(s, 3H). LC/MS(M+1)=268

4-Bromo-2-methoxybenzonitrile

In a 1 L round-bottomed flask, 53.94 g (270 mmol) of4-bromo-2-fluorobenzonitrile was dissolved in 500 mL of THF. Sodiummethoxide (21.99 g, 407 mmol) was added and the mixture was heated toreflux until TLC (SiO₂:CH₂Cl₂) showed complete consumption of startingmaterial. The mixture was poured into 1N HCl and the THF was evaporatedin vacuo. The remaining mixture was extracted with diethyl ether. Theextract was dried (MgSO₄) and filtered over a plug of silica gel. Theplug was eluted with CH₂Cl₂ and the filtrate was evaporated in vacuo toafford 45.56 g (80%) of the product as a white solid. ¹H NMR (500 MHz,CDCl₃) δ 7.42 (d, 1H), 7.17 (dd, 1H), 7.14 (d, 1H), 3.95 (s, 3H).

4-Cyano-3-methoxyphenyl boronic acid (28)

A 3-necked 1 L round-bottomed flask was equipped with an overheadstirrer, and a nitrogen line. The flask was charged with 45.56 g (215mmol) of 4-bromo-2-methoxybenzonitrile, 64 mL (277 mmol) oftri-isopropylborate and 500 mL of THF. The solution was cooled to −78°C. in a dry-ice/acetone bath. n-Butyllithium (2.5M, 110 mL, 275 mmol)was added dropwise via addition funnel. The mixture was stirred for 30minutes and 2N HCl was added. The mixture was stirred for an hour andpoured into water. The mixture was extracted with Et₂O. The organicsolution was backextracted with 1N NaOH. The aqueous layer was washedwith Et₂O and acidified with conc. HCl. The mixture was extracted withEt₂O. The organic extract was dried (MgSO₄) and evaporated in vacuo toafford 20.77 g (55%) of the product as a white solid. ¹H NMR (500 MHz,d6-DMSO) δ 7.68 (d, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 3.95 (s, 3H).

Schemes 7 and 8:

5-Chloro-3-iodo-pyridin-2-ylamine (40)

Iodine (16.28 g, 64 mmol) was added to a mixture of1-amino-5-chloropyridine (8.25 g, 64 mmol) and silver sulfate (20 g, 64mmol) in 400 mL of ethanol and the mixture was stirred at rt for 20 h.The mixture was filtered over celite and the solvent removed in vacuo.The residue was dissolved in DCM (600 mL) and washed with 5% aqueousNaOH (500 mL), water and brine. The organic layer was dried andconcentrated in vacuo to solid residue that was subjected to flashchromatography (20% EtOAc-80% hexanes) to give 9.8 g (60%) of 40. ¹H NMR(500 MHz, CDCl₃) 7.9 (s, 1H), 7.7 (s, 1H), 5.0 (bs, 2H).

5-Chloro-2-(triethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (41)

A mixture of 40 (9.5 g, 37.3 mmol) was dissolved in 320 mL of DMF andtriethylsilylacetylene (20 mL, 112 mmol), Pd₂Cl₂ (dppf)₂ (1.52 g, 1.9mmol), lithium chloride (1.58 g, 37.3 mmol) and 2M Na₂CO₃ (7.9 mL, 74.7mL) were added and the mixture was stirred and refluxed at 90° C. for 15h under nitrogen. Diluted with ethyl acetate-ether mixture (1:1) and theorganic phase washed with water and brine then dried (Na₂SO₄) andconcentrated in vacuo. The residue was subjected to flash chromatography(20% EtOAc/80% hexanes) to give 4.37 g (44%) of the desired product 41.¹H NMR (500 MHz, CDCl₃) 9.4 (bs, 1H), 8.2 (s, 1H), 7.9 (s, 1H), 6.6 (s,1H), 0.9 (t, 9H), 0.75 (q, 6H).

5-Chloro-1H-pyrrolo[2,3-b]pyridine (42)

Compound 41 (4.37 g, 0.0164 mol) was dissolved in THF. Molecular sieve(10 g of 3A) was added followed by TBAF (32.75 mL, 0.0328). The reactionmixture was stirred for 5 h at rt. Diluted with ethyl acetate and washedseveral times with water, brine and the organic layer was dried andconcentrated in vacuo to an oil that was subjected to flashchromatography (30% EtOAc-70% hexanes) to give 02.3 g (90%) of thedesired material 42. ¹H NMR DMSO d₆ 11.8 (bs, 1H), 8.2 (s, 1H), 8.1 (s,1H), 7.5 (s, 1H), 6.5 (s, 1H).

1-(tert-Butyl-dimethyl-silanyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (43)

In a sealed tube equipped with a septa under nitrogen was added 42 (600mg, 0.00396 mol) and 20 mL of dry THF and the solution cooled to 0° C.NaH (110 mg, 0.00435 mol) was added portionwise and after 15 min. ofstirring at 0° C., TBSCl (656 mg, 0.00435 mol) was added. The septa wasreplaced by a Teflon screw cap and the sealed tube heated at 80° C. for3 h. Cooled and neutralized with ammonium chloride solution andextracted with hexanes. The organic phase was dried and concentrated invacuo to an oil that was subjected to a short plug filtration (10%EtOAC-90% hexanes) to give 871 mg (82%) of compound 43. ¹H NMR (500 MHz,CDCl₃) 8.2 (s, 1H), 7.8 (s, 1H), 7.25 (s, 1H), 6.4 (s, 1H), 0.9 (s, 9H),0.6 (s, 6H).

Compound 43 can be brominated at C-3 as previously described in Scheme 3for compound 21.

Compound 19 can be lithiated with, for example, t-BuLi and quenched withDMF to provide the 5-formyl azaindole 44. Compound 19 can also betreated with carbon moxoxide and methanol in the presence of a palladiumcatalyst, for example, Pd(Ph₃P)₄ to provide the 5-carbomethoxy azaindole44. Functionnal group interconversion to an acid, primary, secondary andtertiary amides such as 45 by standard transformations. Compound 44 canbe homologated via, for example, a Wittig reaction to compounds like 49.

Compound 19 can be cyanated with, for example, KCN in heating DMF in thepresence of a catalyst such as, copper or palladium to provide the5-cyano azaindole 46.

Amination of compound 19 with, for example, and amine in the presence ofa palladium catalyst can provide 5-aminated azaindoles such as 48.

Compound 19 can be arylated or heterroarylated using, for example,Suzuki or Stille coupling to provide compound like 47.

In another aspect, other synthetic schemes and compound syntheses areprovided:

5-Chloro-3-iodo-pyridin-2-ylamine (1): A round bottom flask equippedwith an air condenser was charged with 5-chloro pyridin-2-ylamine (26 g,0.2 mol), acetic acid (78 ml) and water (18 ml). This was followed bydropwise addition of concentrated sulphuric acid (2.6 ml), portionwiseaddition of periodic acid (9.5 g, 0.04 mol), and iodine (20 g, 0.08mol). The reaction mixture was vigorously stirred at 80° C. for 6 h andthen allowed to cool the room temperature.

The reaction mixture was poured onto ice (˜700 g). The pH of thesuspension was adjusted to 8-9 with a 5M aqueous NaOH solution. A brownsolid was filtered off and solubilised in EtOAc (1.21). The organic waswashed with a saturated aqueous solution of Na₂S₂O₃, 1M NaOH solutionand brine. The organic was dried over MgSO₄ and concentrated. Theresidue was recristallised from cyclohexane to afford an orange solid(42 g, 80%). ¹H NMR (CDCl₃): 4.8-5.1 (2H, brs), 7.9 (1H, s), 8.0 (1H, s)

5-Chloro-3-(trimethyl-silanylethynyl)-pyridin-2-ylamine (2): A 250 mlround bottom flask was charged with 5-chloro-3-iodo-pyridin-2-ylamine(1) (42 g, 165 mmol), THF (100 ml), copper iodide (315 mg, 1.65 mmol)and PdCl₂(PPh₃)₂ (1.15 g, 1.65 mmol) under nitrogen. Triethylamine (70ml, 0.5 mol), and trimethylsilyl acetylene (30 ml, 0.21 mol). Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was then cooled to 0° C. and diethyl ether was added. Thesuspension was filtered through a celite and thoroughly washed withdiethyl ether. The filtrate was concentrated and pre-absorbed ontosilica gel and purified by column chromatography using as eluent,pentane/DCM 10% to 100%, to afford an off white solid (36 g, 100%). ¹HNMR (CDCl₃): 0.3 (9H, s), 5.0-5.1 (2H, brs), 7.6 (1H, s), 7.9 (1H, s).MS (ES+): 225, 227.

5-Chloro-1H-pyrrolo[2,3-b]pyridine (3): A solution of potassiumtert-butoxide (36 g, 320 mmol) in N-methylpyrrolidone (70 ml) was heatedto 80° C. under nitrogen. A solution of5-chloro-3-(trimethyl-silanylethynyl)-pyridin-2-ylamine (2) (36 g, 160mmol) in NMP (200 ml) was added dropwise via a dropping funnel. Thereaction mixture was stirred at 80° C. for a further fifty minutes. Thereaction mixture was allowed to cool to room temperature. Brine (500 ml)was added to the reaction mixture and extracted with diethyl ether(5×200 ml). The combined organics were washed with brine, dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography, using as eluent pentane/EtOAc 0% to 40%, andfurther recrystallised from cyclohexane to afford the title compound (10g, 41%). 1H NM (CDCl₃) 6.5 (1H, s), 7.4 (1H, s), 8.0 (1H, s), 8.2 (1H,s), 10.4-10.6 (1H, brs). MS (ES+) 153.

3-Bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (4): A solution of bromine(3.5 ml) in chloroform (40 ml) was added dropwise to an ice-coldsolution of the 5-chloro-1H-pyrrolo[2,3-b]pyridine (3) (10 g, 65 mM) inchloroform (260 ml). The reaction mixture was stirred for 60 minutes at0° C. The reaction mixture was then hydrolysed with water and the pH ofthe solution was adjusted to 10. The resulting solid was removed byfiltration, and the aqueous was extracted with dichloromethane. Theorganic was washed with water, dried over magnesium sulfate andconcentrated in vacuo to afford the title compound (10.5 g, 69%). 1H NMR(DMSO-d6) 7.8 (1H, s), 7.9 (1H, s), 8.3 (1H, s)

3-Bromo-5-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (5):Sodium hydride (2.2 g, 54 mmol) was added portionwise to an ice-coldsolution of 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (4) (10.5 g, 45mmol) in dimethylformamide (70 ml) under nitrogen. Thirty minutes later,tosyl chloride (8.7 g, 46 mmol) was added to the reaction mixture andthe reaction mixture was stirred at room temperature for 18 h. Thereaction mixture was hydrolysed with water (˜150 ml) and a brown solidwas obtained by filtration and dried in vacuo to afford the titlecompound (14.8 g, 85%). ¹H NMR (CDCl₃) 2.4 (3H, s), 7.3-7.4 (2H, d),7.8-7.9 (2H, 2s), 8.1-8.2 (2H, d), 8.4 (1H, s); MS(ES+) 387

5-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl-1H-[2,3-b]pyridine(6): A 500 ml round bottom flask was charged under nitrogen with3-bromo-5-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (5)(6.9 g, 18 mmol), bispinacolato diboron (6.9 g, 27 mmol), PdCl₂(dppf)₂(1.5 g, 1.8 mmol), potassium acetate (5.3 g, 54 mmol) anddimethoxyethane (100 ml). The reaction mixture was stirred at 90° C. for18 h. The reaction mixture was diluted with ethyl acetate (200 ml) andwashed with brine. The organic was dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by columnchromatography, using as eluent pentane/EtOAc 0% to 20% and thentriturated with pentane to afford the title compound (4 g, 50%). ¹HNMR(CDCl₃) 1.4 (9H, s), 2.4 (3H, s), 7.2 (2H, d), 8.00-8.05 (2H, d),8.10 (2H, s), 8.3 (1H, s). MS(ES+) 433

(6-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (7): A microwave vial wascharged with 4-chloro benzylamine (700 mg; 5 mmol; 5 equivalents) and2,6-dibromo pyridine (238 mg, 1 mmol). The reaction mixture was stirredin the microwave at 150° C. for three times ten minutes (200 W maximum).The reaction mixture was diluted with diethyl ether (50 ml), washed with10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine.The organic was dried over magnesium sulfate and, after filtration,concentrated in vacuo to afford an oil as the title compound (300 mg,100% yield). LC/MS: 299 [M+H]

(4-Chloro-benzyl)-[6-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3yl)-pyridin-2yl]-amine(8): A microwave vial was charged with(6-bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (300 mg, 1 mmol),5-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl-1H-[2,3-b]pyridine(7) (215 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium (60 mg,0.05 mmol), 2M sodium hydroxide (0.75 ml) and dimethoxyethane (5 ml).The suspension was degassed with nitrogen. The reaction mixture wasstirred in the microwave at 130° C. for ten minutes (200 W maximum). Itwas then diluted with ethyl acetate (60 ml), washed with brine twice,dried over magnesium sulfate and, after filtration, concentrated invacuo. The compound was purified by flash chromatography (eluent:petroleum ether/ethyl acetate 60/40) to afford 50 mg of the tosylprotected title compound. This residue was taken up in a mixture ofmethanol and tetrahydrofuran (1/3 ml). 1M sodium hydroxide solution (1ml) was added to the reaction mixture, which was then stirred at roomtemperature for three hours. The reaction mixture was then concentratedin vacuo and the residue was triturated with methanol. The suspensionwas filtered to afford the title compound (35 mg, 10%). 1H NMR(DMSO-d6): 4.60-4.70 (2H, m), 6.35-6.40 (1H, d), 7.05-7.10 (1H, d),7.20-7.25 (1H, t), 7.35-7.45 (4H, m), 8.15-8.20 (2H, m), 8.55-8.60 (1H,s), 12.5 (1H, s). LC/MS: 369 [M+H], 367 [M−H]

Table 3 below depicts data for certain exemplary compounds. Compoundnumbers correspond to those compounds depicted in Table 1. A “-”indicates that the measurement was not made.

TABLE 3 LC_MASS_(—) Cmpd# PLUS NMR_RESULT 1 — 8.9 1H, d; 8.35 1H, s;8.25 1H, d; 8.1 1H, d; 7.2 1H, dd, 7.1 1H, d; 6.5 1H s 2 309.10 CDCl39.2(m, 1H) 9.18(s, 1H) 8.51(s, 1H), 8.16(dd, J=5.4, 1.0, 1H) 7.34(dd,J=8.0, 5.4, 1H), 7.25(m 1H) 7.19(m, 1H) 7.03(m, 1H) 6.85(s, 1H) 3 324.00MeOD(500MHz) 8.76(s, 1H) 8.45(s, 1H) 8.43(s, 1H), 8.34(s, 1H) 7.66(m,1H) 7.40(m, 1H) 7.38(m, 1H), 7.27(m, 2H) 4 288.00 MeOD, 7.2s(1H),7.25t(1H), 7.35m(1H), 7.5t(2H), 7.65 d(2H), 8.25s(1H), 8.4m(2H),8.7s(1H) 5 310.00 MeOD, 0.6m(2H), 1.0m(2H), 1.6s(3H), 1.8m(1H), 2.1m(1H), 2.3d(1H), 2.6d(1H), 4.3s(1H), 6.0m(2H), 6.95 s(1H), 7.05m(1H),7.5m(2H) 6 212.00 MeOD, 7.05s(1H), 7.35m(1H), 8.2s(1H), 8.4m(2H), 8.55s(1H) 7 302.00 MeOD, 4.8s(2H), 7.05s(1H), 7.2-7.6m(6H), 8.2s(1H), 8.4m(2H), 8.55s(1H) 8 240.10 1H 8.94, 1H 8.19, 1H 8.14, 2H 7.25, 1H 7.02,2H 3.52,, 3H 1.31 9 337.00 MeOD, 2.0bs(2H), 2.1s(3H), 3.6m(2H),3.8-4.3bm(6H), 7.1 d(1H), 7.3m(1H), 8.2d(1H), 8.35m(2H), 8.65d(1H) 10332.00 MeOD, 3.8s(3H), 4.7bs(2H), 7.0m(3H), 7.35m(4H), 8.2 s(1H),8.4m(2H), 8.6bs(1H) 11 308.00 MeOD, 1.05m(2H), 1.3m(3H), 1.7m(2H),1.75-1.9m(4H), 3.5d(2H), 7.0s(1H), 7.3(1H), 8.1s(1H), 8.35d(1H), 8.4d(1H), 8.6s(1H) 12 310.00 MeOD 1.4m(2H), 1.7m(2H), 2.0m(1H), 2.65s(1H),3.45 m(2H), 3.6m(1H), 4.0d(2H), 7.0s(1H), 7.35m(1H), 8.2 s(1H),8.35d(1H), 8.45m(1H), 8.6s(1H) 13 240.00 MeOD; 1.3t(3H), 3.65m(2H),7.0s(1H), 7.3m(1H), 8.2 s(1H), 8.4d(2H), 8.6m(1H) 14 256.00 MeOD;3.7-3.9dm(4H), 7.0s(1H), 7.3m(1H), 8.1s(1H), 8.4 d(2H), 8.6bs(1H) 15360.10 ¹H NMR 500MHz (DMSO-d6) 12.35ppm, 1H, s;, 11.02ppm, 1H, s;8.88ppm, 1H, s; 8.63ppm, 1H, d;, 8.42ppm, 1H, s; 8.33ppm, 2H, m;7.25ppm, 2H, m;, 6.97ppm, 2H, m; 6.87ppm, 1H, d; 3.78ppm, 2H, s;,3.77ppm, 3H, s. 16 302.00 DMSO d₆ 8.7(bs, 1H); 8.4(bs, 1H); 8.25(d, 1H);8.1(d, 1H); 7.4(m, 2H); 7.25(m, 3H); 7.2(bs, 1H); 7.15(bs, 1H); 4.7(bs,2H) 17 313.00 DMSO, 7.2 q(2H), 8.3mm(3H), 8.6d(2H), 8.85dd(2H), 9.1s(1H), 12.35bs(2H) 18 336.00 MeOD, 4.8s(2H), 7.0s(1H), 7.3bs(5H),8.1s(1H), 8.3 m(2H), 8.6s(1H) 19 295.00 — 20 337.00 — 21 347.90 — 22347.90 — 23 365.90 — 24 422.90 — 25 343.95 — 26 328.00 MeOD, 3.1bm(2H),4.0-4.4bd(2H), 5.0-5.3bs(2H), 7.25 s(1H), 7.3-7.35m(4H), 7.4m(1H),8.3s(1H), 8.4d(1H), 8.5 d(1H), 8.7s(1H) 27 366.10 ¹H NMR 500MHz(DMSO-d6) 12.33ppm, 1H, s; 11.03ppm, 1H, s; 8.86ppm, 1H, s; 8.62ppm, 1H,m; 8.43ppm, 1H, s; 8.29ppm, 2H, m; 7.45ppm, 2H, m; 7.25ppm, 1H, m;7.20ppm, 2H, m; 3.87ppm, 2H, s;. 28 348.00 ¹H NMR 500MHz (DMSO-d6)12.42ppm, 1H, s; 11.05ppm, 1H, s; 9.72ppm, 1H, s; 8.89ppm, 1H, s;8.63ppm, 1H, m; 8.43ppm, 1H, s; 8.31ppm, 2H, m; 7.25ppm, 6H, m; 1H, m;3.87ppm, 2H, s; 3.00ppm, 3H, s. 29 423.10 ¹H NMR 500MHz (DMSO-d6)12.33ppm, 1H, s; 11.00ppm, 1H, s; 8.84ppm, 1H, s; 8.59ppm, 1H, m;8.45ppm, 1H, s; 8.30ppm, 2H, m; 7.30ppm, 6H, m; 3.83ppm, 2H, s. 30330.00 ¹H NMR 500MHz (DMSO-d6) 12.35ppm, 1H, s; 11.10ppm, 1H, s;8.88ppm, 1H, s; 8.62ppm, 1H, m; 8.42ppm, 1H, s; 8.31ppm, 2H, m; 7.30ppm,5H, m; 3.90ppm, 2H, s; 31 348.00 ¹H NMR 500MHz (DMSO-d6) 12.35ppm, 1H,s; 11.10ppm, 1H, s; 8.88ppm, 1H, s; 8.62ppm, 1H, m; 8.42ppm, 1H, s;8.31ppm, 2H, m; 7.30ppm, 5H, m; 3.90ppm, 2H, s; 32 309.00 12.25(s, 1H),8.67(d, 1H), 8.40(s, 1H),, 8.30(d, 1H), 8.27(d, 1H), 7.23dd, 1H),,7.09(d, 1H), 4.63(d, 2H), 3.30(s, 2H), 2.80(m, 2H), 2.45(m, 1H), 1.07(d,6H), DMSO-d6, 33 351.00 12.28(s, 1H), 8.72(d, 1H), 8.42(s, 1H),, 8.31(d,1H), 8.28(d, 1H), 7.25(dd, 1H),, 7.14(d, 1H), 4.71(d, 2H), 4.10-4.70(m,2H), 3.30(s, 1H), 3.12(s, 2H), 2.09(s, 3H),, 1.21(m, 6H), DMSO-d6, 34308.00 8.90(s, 1H), 8.60(s, 1H), 8.39(m, 1H),, 8.01(m, 1H), 7.33(m, 2H),4.80(s, 10H, solvent),, 3.55(m, 1H), 3.30(m, 14H, solvent), 1.92(m, 2H),1.81(m, 3H), 1.72(m, 1H),, 1.25-1.40(m, 3H), 1.08-1.25(m, 2H), MeOH-d4,35 385.00 MeOD, 1.8-2.8bm(2H), 2.35bm(2H), 3.2bm(1H), 3.6(2H),4.5-4.5bs(3H), 7.0bs(1H), 7.3m(1H), 7. s(5H), 8.2s(1H), 8.3m(2H),8.6s(1H) 36 367.00 MeOD, 1.25t(3H), 1.55 q(2H), 2.1d(2H), 3.1m(2H), 4.15m(4H), 4.6m(1H), 7.0s(1H), 7.3m(1H), 8.2s(1H), 8.3 d(1H), 8.4d(1H),8.6s(1H) 37 337.00 12.32(s, 1H), 9.3-10.5(s, 4H), 9.01(d, 1H),, 8.51(s,1H), 8.48(d, 1H), 8.19(d, 1H),, 7.53(m, 1H), 7.25(d, 1H), 4.82(m,1/2H),, 4.25-4.53(m, 2 1/2H), 3.81-3.93(m, 1/2H), 3.58-3.71(m, 1 1/2H),3.14-3.58(m, 1 1/2H),, 2.12(s, 3H), 1.18-1.40(m, 3H), CD3CN, 38 337.0012.4(s, 1H), 8.96(d, 1H),, 8.48(s, 1H), 8.40(d, 1H), 8.12(d, 1H),,7.49(m, 1H), 7.20(d, 1H), 4.8(m, 1/2H),, 4.2-4.5(m, 2 1/2H),3.79-3.91(m, 1/2H), 3.58-3.69(m, 1 1/2H), 3.12-3.58(m, 1 1/2H),, 2.1(s,3H), 1.12-1.35(m, 3H),CD3CN,, 39 351.00 MeOD, 1.4s(1H), 1.7t(2H),2.3d(2H), 7.0s(1H), 7.3m(1H), 8.1s(1H), 8.3d(1H), 8.35d(1H), 8.6s(1H) 40378.90 12.9(s, 1H); 9.1(s, 1H); 8.9(s, 1H); 8.8(s, 1H); 8.7(bs, 2H);8.5(d, 1H); 8.3(d, 1H); 7.6(bs, 1H); 7.4(m, 6H); 4.7(s, 2H) 41 335.90CDCl₃ 8.7(bs, 2H); 8.4(bs, 2H); 8.3(s, 1H); 7.4(m, 5H); 4.8(s, 2H) 42362.00 10.94(m, 1H), 8.96(d, 1H), 8.71(s, 1H), 8.55(s, 1H),, 8.19(dd,1H), 7.24(d, 1H), 4.5-6.0(6H), 3.7-4.3(m, 6H),, 3.60(m, 2H), 2.1(s, 3H)43 302.00 MeOD, 4.95bs(2H), 6.6d(1H), 7.2m(1H), 7.3-7.5mm(5H), 8.0d(1H),8.3d(1H), 8.4s(1H), 8.55d(1H) 44 230.10 1H 8.45, 3H 8.35, 2H 7.82, 1H7.25 45 250.00 10.00(s, 1H), 8.32(m, 2H), 7.83(s, 1H), 7.65(d, 1H),,7.40(m, 2H), 7.20(dd, 1H), 4.02(s, 3H),, CD3CN 46 268.00 11.99(s, 1H),8.32(d, 1H), 8.24(m, 1H),, 8.01(m, 1H), 7.88(d, 1H), 7.59(s, 1H),,7.40(s, 1H), 7.37(m, 2H), 7.15(dd, 1H),, 4.00(s, 3H),, DMSO-d6 47 268.00— 48 238.00 11.98(s, 1H), 8.32(d, 1H), 8.26(m, 1H), 8.15(s, 1H),,8.00(s, 1H), 7.91(d, 1H), 7.82(d, 1H), 7.71(d, 1H),, 7.47(t, 1H),7.34(s, 1H), 7.16(dd, 1H), DMSO-d6 49 238.00 11.97(s, 1H), 8.29(d, 1H),8.21(d, 1H), 7.92(d, 1H),, 7.85(d, 2H), 7.71(d, 2H), 7.17(s, 1H),7.10(dd, 1H), DMSO-d6 50 292.00 11.97(s, 1H), 8.48(s, 1H), 8.29(m, 2H),8.00(d, 1H),, 7.88(d, 1H), 7.71(dd, 1H), 7.61(s, 1H), 7.27(d, 1H),,7.21(dd, 1H), 4.01(s, 3H), DMSO-d6 51 301.00 — 52 301.00 — 53 255.00 —54 285.00 — 55 241.00 —

Table 4 below depicts data for certain exemplary compounds. Compoundnumbers correspond to those compounds depicted in Table 2. A blankindicates that the measurement was not made.

TABLE 4 LC_MASS_(—) Cmpd PLUS RT No. M+1 (obs) NMR_RESULT (1H NMR)(mins) 1 380.00 12.68(m, 1H), 9.20(s, 1H), 8.82(s, 1H), 8.62(m, 1H),1.45 8.28(m, 1H), 8.05(s, 1H), 7.35(s, 1H), 7.25(m, 1H), 3.6-4.2(m, 6H),3.45(m, 2H), 1.7-2.1(m, 5H) DMSO-d6 2 379.00 1.70 3 414.00 2.30 4 335.902.60 5 371.00 2.10 6 MeOD 5.0s(2H), 7.1s(1H), 7.3m(1H), 7.6m(1H),8.1d(1H), 8.2 s(1H), 8.3-8.4m(2H), 8.55d(1H), 8.6s(1H), 8.7s(1H) 7 MeOD5.1s(2H), 7.25m(1H), 7.35m(1H), 7.9d(2H), 8.25s(1H), 8.4d(2H),8.65s(1H), 8.7d(2H) 8 385.00, 385.00 11.35(s, 1H), 9.25(s, 1H), 9.10(s,1H), 9.00(s, 1H), 2.02, 8.69(d, 1H), 7.82(d, 1H), 5.00(m, 2H), 4.10(m,2H), 2.73(s, 4.63 3H), 1.91(m, 6H)DMSO-d6, 12.5(s, 1H), 8.70(s, 1H),8.50(s, 1H), 8.31(s, 1H), 8.29(d, 1H), 7.10(d, 1H), 4.66(d, 2H),4.2-4.6(m, 2H), 3.15(m, 2H), 2.09(s, 3H), 1.20(m 6H) DMSO-d6 9 328.0012.73(s, 1H), 8.71(s, 1H), 8.67(s, 1H), 8.32(s, 1H), 8.25(d, 2.35 1H),7.21(m, 1H), 3.65-3.95(m, 4H), 1.82(m, 4H), 1.53(m, 4H)DMSO-d6 10 346.002.23 11 328.00 12.75(s, 1H), 8.71(s, 1H), 8.68(s, 1H), 8.35(s, 1H),8.25(d, 2.40 1H), 7.22(d, 1H), 4.62(m, 2H), 3.10(m, 2H), 1.75(m, 3H),1.20(m, 2H), 0.91(m, 3H)DMSO-d6 12 332.00 DMDO d6 12.6(s, 1H); 9.5(bs,1H); 8.8(s, 1H); 8.4(s, 2.10 1H); 8.1(s, 1H); 7.8(bs, 1H): 7.4(m, 5H);7.1(bs, 1H); 4.8(d, 2H), 3.8(s, 3H) 13 346.00 DMSO d6 12.8(s, 1H);9.4(bs, 1H); 8.8(s, 1H); 8.3(s, 2.20 1H); 8.2(s, 1H); 7.9(bs, 1H):7.4(m, 5H); 7.2(bs, 1H); 5.2(bs, 1H), 3.8(s, 3H); 1.5(d, 3H) 14 346.00DMSO d6 12.8(s, 1H); 9.4(bs, 1H); 8.8(s, 1H); 8.3(s, 2.20 1H); 8.2(s,1H); 7.9(bs, 1H): 7.4(m, 5H); 7.2(bs, 1H); 5.2(bs, 1H), 3.8(s, 3H);1.5(d, 3H) 15 413.00 MeOD 1.2s(3H), 1.9m(1H), 2.2m(1H), 2.55m(1H),2.6s(3H), 1.31 1.2-3.4m(2H), 3.55m(1H), 3.8m(1H), 4.5s(2H), 5.5bs(0.7H), 7.1s(1H), 7.35m(1H), 7.5-7.6mm(5H), 8.3 s(1H), 8.4-8.5mm(2H),8.7s(1H) 16 320.00 MeOD 1.98 4.9s(2H), 7.0-7.6mm(7H), 8.2s(1H),8.3d(1H), 8.7s(1H) 17 MeOD 1.2d(3H), 1.9m(1H), 2.2m(1H), 2.4s(1H),2.6m(3H), 3.0 s(1H)3.5m(1H), 3.8m(1H), 7.1s(1H), 7.2d(1H), 7.35 m(1H),7.7d(1H), 8.3s(1H), 8.4d(1H), 8.5d(1H), 8.7 s(1H) 18 380.00, 380.0011.95(1H), 10.47(s, 3H), 8.51(s, 1H), 1.98, 8.17(s, 1H), 8.09(s, 1H),7.77(t, 1H), 2.02 7.18(d, 1H), 6.87(d, 1H), 4.4-4.6(s, 2H) 3.99(s, 3H),3.32(m, 2H), 2.13(s, 3H), 1.35(m, 6H) DMSO-d6, 9.82(s, 1H), 8.32(d, 1H),8.08(d, 1H), 7.93(s, 1H), 7.58(t, 1H), 7.20(d, 1H), 6.66(d, 1H),4.2-4.7(m, 4H), 3.91(s, 3H), 3.12(m, 2H), 2.10(s, 3H), 1.35(m, 6H) CD3CN19 384.00, 384.00, 10.75(s, 1H), 8.46(s, 1H), 8.39(s, 1H), 2.39, 384.00,384.00, 8.10(s, 1H), 7.91(t, 1H), 7.19(d, 1H), 2.70, 384.00, 384.00,7.02(d, 1H), 6.25-6.75(s, 9H), 4.4-46(s, 2H) 3.26, 384.00, 384.00,4.10(d, 2H), 3.49(m, 2H), 2.18(s, 3H), 1.38(d, 6H) 2.42, 384.00, 384.00,DMSO-d6, good, good, good, 11-12.2(s, 2H), 10.6-11.0(s, 3.22, 384.001H), 8.54(s, 1H), 2.39, 8.35(s, 1H), 8.05(s, 1H), 7.69(t, 1H), 7.11(d,1H), 3.35, 6.89(d, 1H), 4.2-4.7(s, 2H), 4.18(d, 2H), 3.35(m, 2H), 3.38,2.17(s, 3H), 1.38(m, 6H) 3.32, CD3CN, 12.20(s, 1H), 8.71(s, 1H), 8.25(d,2H), 7.55(t, 3.32, 1H), 3.32 7.17(d, 1H), 6.69(d, 1H), 4.0-4.5(s, 2H),4.29(d, 2H), 3.05(m, 2H), 2.09(s, 3H), 1.28(m, 6H), 12.24(s, 1H),8.73(s, 1H), 8.27(d, 2H), 7.58(t, 1H), 7.18(d, 1H), 6.71(d, 1H),4.2-4.5(m, 14H), 3.08(m, 2H), 2.32(s, 3H), 2.09(s, 3H), 1.28(s, 6H)DMSO-d6, 12.20(s, 1H), 8.72(s, 1H), 8.25(d, 2H), 7.57(t, 1H), 7.19(d,1H), 6.71(d, 1H), 4.3-4.7(s, 1H), 4.3(d, 2H), 3.27(s, 9H), 3.07(m, 2H),2.70(q, 1H), 2.10(s, 3H), 1.29(s, 6H) DMSO-d6 DMSO-d6, 12.31(s, 1H),8.70(s, 1H), 8.29(m, 2H), 7.65(m, 1H), 7.20(d, 1H0, 6.80(d, 1H),6.5-6.8(s, 4H), 4.28(d, 2H), 4.0-4.6(s, 1H), 3.15(m, 2H), 2.41(s, 6H),good 20 335.00 10.55(s, 1H), 8.38(m, 1H), 8.30(m, 2H), 2.39 7.89(t, 1H),7.41(m, 4H), 7.34(m, 1H), 7.12(d, 1H), 6.73(d, 1H), 4.7-5.7(s, 4H)4.60(s, 2H) CD3CN 21 336.00 MeOD 2.20 2.65s(0.3H, DMSO), 4.9s(2H),7.1s(1H), 7.3-7.5m(6H), 8.2s(1H), 8.4-8.5m(2H), 8.7s(1H) 22 370.00 MeOD2.60 4.9s(2H), 7.1s(1H), 7.3bs(1H), 7.6-7.8m(5H), 8.2s(1H), 8.4m(2H),8.675s(1H) 23 378.00 MeOD 2.60 2.65s(0.9H, DMSO)4.9s(2H), 7.1s(1H),7.3-7.5m(6H), 7.6-7.7m(5H), 8.2s(1H), 8.4m(2H), 8.65s(1H) 24 367.00 DMSOd6 12.5(bs, 1H); 8.5(bs, 1H); 8.2(m, 2H); 8.0(d, 1.70 1H); 7.3(d, 1H);4.0(bs, 2H); 3.9(s, 3H); 3.8(bs, 2H); 3.5(t, 2H); 2.5(s, 3H); 1.9(bs,2H) 25 381.10, 381.40 DMSO d6 12.5(bs, 1H); 8.4(s, 1H); 8.3(d, 1H);8.25(s, 2.00, 1H); 8.1(s, 1H); 7.3(d, 1H); 4.7(app d, 2H); 3.9(s, 3H);2.00 3.2(bd, 2H); 2.1(s, 3H); 1.2(bs, 6H), DMSO d6 12.3(bs, 1H); 8.5(s,1H); 8.25(m, 2H); 8.1(d, 1H); 7.2(d, 1H); 4.65(d, 4H); 3.9(s, 3H);3.2(bd, 2H); 2.1(s, 3H); 1.2(bs, 6H) 26 316.00 H1 MeOD: 1.3m(1H),3.4s(3H), 5.1s(2H), 7.0s(1H), 7.1-7.4 2.10 m(7H), 8.1s(1H), 8.3d(1H),8.6s(1H) 27 320.00 H1 DMSO: 4.7s(2H), 7.2t(4H), 7.3m(1H), 7.55m(2H),2.00 8.3m(3H), 8.7s(1H), 9.1-9.3bs(0.75H) 28 317.00 H1 MeOD: 1.8bs(2H),4.7s(2H), 6.7-6.85mm(4H)7.0-7.2 1.60 m(1H), 7.3m(1H), 8.15s(1H),8.3m(2H), 8.6s(1H) 29 338.00 MeOD 2.00 4.9s(2H), 6.9m(1H), 7.0m(2H),7.2s(1H), 7.3m(1H), 8.2 s(1H), 8.4m(2H), 8.65s(1H) 30 403.20 CD3CN,10.7(bs, 1H); 8.15(s, 1H); 8-8.1(m, 3H); 7(d, 1.90 1H); 3.8-4.05(bs,4H); 3.8(s, 3H); 3.6(bs, 2H); 3.3(t, 2H); 2.8(s, 3H); 2.4(s, 2H) 31417.20 CD3CN, 10.7(s, 1H); 8.15(s, 1H); 8(m, 3H); 7(d, 1H); 2.003.8-4(bs, 4H); 3.85(s, 3H); 3.6(bs, 2H); 3.3(m, 4H); 2.9(m, 2H); 1.1(m,3H) 32 427.00 12.33(s, 1H), 8.78(d, 1H), 8.37(d, 1H), 8.28(d, 1H), 2.247.87(s, 1H), 7.69(d, 1H), 7.49(s, 1H), 7.44(d, 1H), 4.37(s, 2H),3.5-4.2(m, 14H), 3.10(m, 2H), 2.08(s, 3H), 1.32(m, 6H) DMSO-d6 33 397.30DMSO-d6 12.25(1H, bs); 8.5(1H, s); 8.3(1H, d); 8.2(1H, 2.10 d); 8.05(1H,d); 7.15(1H, bs); 4.0(4H, m); 3.9(3H, s); 3.8-4.0(4H, bm); 3.6-3.8(2H,bs); 3.4(2H, bs); 1.1(3H, bm) 34 411.30 DMSO-d6 12.25(1H, bs); 8.5(1H,s); 8.3(1H, d); 8.2(1H, 2.30 d); 8.05(1H, d); 7.15(1H, bs); 3.85(3H, s);3.7-4.0(8H, bm); 3.6-3.8(2H, bs); 3.4(2H, bs); 1.5(2H, bs); 0.8(3H, bm)35 408.30, 408.29 DMSOd6 12.4(s, 1H); 9.5(s, 1H); 8.8(s, 1H); 8.3(s,1H); 2.90, 7.5(dd, 1H); 7.2(d, 1H); 6.7(d, 1H); 4.6(bs, 2H); 4.3(d, 2.942H); 3.9(s, 3H); 3.1(bd, 2H); 2.1(s, 3H); 1.2(bs, 6H) 36 428.00 12.41(s,1H), 8.78(s, 1H), 8.41(s, 1H), 8.29(s, 1H), 2.38 7.95(d, 1H), 7.45(d,1H), 6.3-7.5(s, 1H), 4.39(s, 2H), 3.69(m, 2H), 3.23(m, 2H), 2.05(s, 3H),1.29(m, 6H) DMSO-d6 37 465.40, 465.30 DMSOd6 11.9(s, 1H); 9.4(s, 1H);9.2(s, 1H); 8.2(s, 1H); 3.10, 7.5(dd, 1H); 7.2(d, 1H); 6.6(d, 1H);4.4(bs, 4H); 3.1(bs, 3.10 2H); 2.1(s, 3H); 1.5(s, 9H); 1.2(bs, 6H) 38365.20 8.9(s, 1H); 8.4(s, 1H); 8.2(s, 1H); 7.7(dd, 1H); 7.2(d, 2.53 1H);6.9(d, 1H); 4.4(bs, 4H); 3.3(bs, 2H); 2.2(s, 3H); 1.4(bs, 6H) 39 315.10DMSO-d6: 12.3(1H, bs); 8.3(2H, m); 8.2(1H, bs); 7.8(1H, 2.30 bs);7.5(6H, m); 6.8(1H, bs); 4.7(2H, s); 4-4.5(1H, bs); 2.3(3H, s) 40 350.09DMSO-d6: 11.9(bs, 1H); 8.5(d, 1H); 8.2(s, 1H); 8.1(s, 1.90 1H); 7.5(t,1H); 7.1(t, 1H); 6.5(d, 1H); 3.9-4.5(bs, 1H); 4.0(t, 1H); 3.7(m, 4H);3.4(dt, 2H); 2.4(s, 3H); 2.1(s, 3H); 1.9(m, 2H) 41 364.20 DMSO-d6:11.9(s, 1H); 8.5(s, 1H); 8.2(s, 1H); 8.1(s, 2.40 1H); 7.6(dd, 1H);7.2(d, 1H); 6.7(d, 1H); 4.5-5.4(bs, 1H); 4.3(d, 4H); 3.1(bd, 2H); 2.4(s,3H); 2.1(s, 3H); 1.3(bs, 6H) 42 379.00 12.6-13.0(s, 1H), 12.38(s, 1H),8.65(s, 1H), 3.18 8.61(m, 1H), 8.40(m, 1H), 8.21(m, 1H), 8.06(d, 1H),7.49(d, 2H), 7.31(t, 2H), 7.21(t, 1H), 7.18(d, 1H), 6.1-6.9(s, 1H),4.88(m, 2H), 3.4-4.7(s, 2H) DMSO-d6 43 393.00 12.39(s, 1H), 8.60(s, 1H),8.50(t, 1H), 8.41(s, 1H), 3.92 8.22(s, 1H), 8.09(d, 1H), 7.39(m, 2H),7.29(m, 2H), 7.20(m, 1H), 6.3-6.8(m, 3H), 4.90(d, 2H), 3.85(s, 3H)DMSO-d6 44 379.00 12.12(s, 1H), 8.20(s, 1H), 8.10(s, 1H), 7.82(m, 2H),2.20 7.32(m, 3H), 7.21(m, 2H), 6.50(d, 1H), 4.60(s, 2H), 3.8-4.5(s, 8H)DMSO-d6 45 393.00 9.94(s, 1H), 8.20(d, 2H), 7.88(d, 1H), 7.73(s, 1H),2.52 7.31-7.42(m, 4H), 7.26(t, 1H), 6.44(d, 1H), 6.27(m, 1H), 4.68(d,2H), 3.70(s, 3H) CD3CN 46 378.00 mixture 2.94 47 394.27 DMSOD6 12.3(s,1H); 9.4(s, 1H); 8.8(s, 1H); 8.2(s, 1H); 2.47 7.5(dd, 1H); 7.2(d, 1H);6.7(d, 1H); 4.4(d, 4H); 3.1(bd, 2H); 2.1(s, 3H); 1.2(bs, 6H) 48 319.20DMSOd6 12.3(bs, 1H); 8.4(bd, 1H); 8.3(d, 2H); 7.6(bs, 2.30 1H); 7.5(m,4H); 7.2(dd, 1H); 7.1(bd, 1H); 6.5(bs, 1H); 4.5(s, 2H) 49 354.30 DMSOd612.2(bs, 1H); 8.4(app.t, 1H); 8.2(m, 2H); 7.5(dd, 2.20 1H); 7.1(dd, 1H);6.5(bs, LH); 3.9(t, 1H); 3.8-3.6(m, 4H); 3.4(dt, 2H); 2.1 and 1.8(s,3H); 2.0(t, 1H) 50 368.40 DMSO D6 12.1(s, 1H); 8.5(dd, 1H); 8.2(s, 2H);7.6(dd, 2.90 1H); 7.2(d, 1H); 6.8(d, 1H); 4.3(bd, 4H); 3.1(db, 2H);2.1(s, 3H); 1.2(bs, 6H) 51 462.00 11.60(s, 1H), 8.70(s, 1H), 8.48(s,1H), 8.11(s, 1H), 1.84 7.82(t, 1H), 7.15(d, 1H), 7.1-8.1(s, 4H), 6.95(d,1H), 4.55(s, 2H), 4.14(m, 2H), 3.68(m, 6H), 3.39(m, 2H), 2.15(s, 3H),1.38(m, 6H) CD3CN 52 490.00 11.29(s, 1H), 8.90(s, 1H), 8.50(s, 1H),8.61(m, 2H), 1.89 8.11(s, 1H), 7.68(t, 1H), 7.12(d, 1H), 6.78(d, 1H),4.0-4.5(m, 12H), 3.40(m, 2H), 3.27(m, 4H), 2.15(s, 3H), 1.25-1.45(m,12H) 53 436.40 DMSO d6 12.4(s, 1H); 9.4(s, 1H); 8.8(s, 1H); 8.3(s, 1H);3.40 7.5(t, 1H); 7.2(d, 1H); 6.7(d, 1H); 5.2(sept, 1H); 4.3(bs, 4H);3.1(bs, 2H); 2.1(s, 3H); 1.3(d, 6H0; 1.2(bs, 6H) 54 461.00 55 475.00 56462.00 57 476.00 58 475.00 59 407.00 60 421.00 61 499.30 DMSO-d6:11.9ppm (s, 1H), 10.2(s, 1H), 9.2(s, 1H), 8.2(s, 3.40 1H), 8.15(s, 1H),7.5(t, 1H), 7.15-7.25(dd, 4H), 7.15(s, 1H), 6.7(d, 1H), 4.2-4.8(bs, 4H),3.0(bd, 2H), 2.5(s, 6H), 2.3(s, 3H), 2.0(s, 3H) 62 451.30 DMSO-d6:11.9ppm (s, 1), 9.6(s, 1H), 9.1(s, 1H), 8.15(s, 2.90 1H), 8.1(s, 1H),7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.35(m, 4H), 4.1(t, 2H), 3.05(bd,2H), 2.1(s, 3H), 1.7(m, 2H), 1.3(bs, 6H), 0.95(t, 3H) 63 465.40 DMSO-d6:11.9ppm (s, 1H), 9.6(s, 1H), 9.1(s, 1H), 8.15(s, 3.20 1H), 8.1(s, 1H),7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.35(m, 4H), 3.9(d, 2H), 3.05(bd,2H), 2.1(s, 3H), 1.9(m, 1H), 1.3(bs, 6H), 0.95(d, 6H) 64 479.40 DMSO-d6:11.9ppm (s, 1H), 9.6(s, 1H), 9.1(s, 1H), 8.15(s, 3.40 1H), 8.1(s, 1H),7.5(t, 1H, 7.1(d, 1H), 6.7(d, 1H), 4.35(m, 4H), 3.85(s, 2H), 3.05(bd,2H), 2.1(s, 3H), 1.3(bs, 6H), 0.95(s, 9H) 65 451.40 DMSO-d6: 11.9ppm (s,1H), 9.6(s, 1H), 9.1(s, 1H), 8.15(s, 2.90 1H), 8.1(s, 1H), 7.5(t, 1H),7.1(d, 1H), 6.7(d, 1H), 4.9(q, 1H), 4.35(m, 4H), 3.05(bd, 2H), 2.1(s,3H), 1.3(m, 12H) 66 423.30 DMSO-d6: 11.9ppm (s, 1H), 9.6(s, 1H), 9.1(s,1H), 8.15(s, 2.40 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H),4.35(m, 4H), 3.7,(s, 3H), 3.05(bd, 2H), 2.1(s, 3H), 1.3(bs, 6H) 67428.00 12.31(s, 1H), 8.71(d, 1H), 8.41(d, 1H), 8.29(d, 1H), 7.56(s, 3.201H), 7.07(s, 1H), 4.0-4.8(m, 4H), 3.3-3.9(m, 20H), 3.13(m, 2H), 2.10(s,3H), 1.16(m, 6H) 68 427.00 12.54(s, 1H), 8.50(d, 1H), 8.35(d, 1H),8.31(d, 1H), 8.09(s, 3.70 1H), 8.07(s, 1H), 4.0-5.4(m, 9H), 3.3(m, 2H),2.09(s, 3H), 1.26(m, 6H) 69 485.30 DMSO d6 11.9(s, 1H), 10.3(s, 1H),9.2(s, 1H), 8.25(s, 3.20 1H), 8.15(s, 1H), 7.5(t, 1H), 7.45(t, 2H),7.25(d, 3H), 7.15(d, 1H), 6.7(d, 1H), 4.0-4.8(bs, 4H), 3.0(bd, 2H),2.0(s, 3H), 1.2(bs, 6H) 70 437.30 DMSO d6 11.8(s, 1H), 9.6(s, 1H),9.1(s, 1H), 8.2(s, 1H), 3.20 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.7(d,1H), 4.4(m, 4H), 4.15(q, 2H), 3.0(bd, 2H), 2.0(s, 3H), 1.25(m, 9H) 71515.30 DMSO d6 11.9(s, 1H), 10.2(s, 1H), 9.2(s, 1H), 8.2(s, 3.20 1H),8.15(s, 1H), 7.5(t, 1H), 7.1(m, 3H), 7.0(d, 2H), 6.7(d, 1H), 4.0-4.8(bs,4H), 3.8(s, 3H), 3.0(bd, 2H), 2.0(s, 3H), 1.2(m, 6H) 72 445.00 12.17(s,1H), 8.41(d, 1H), 8.27(d, 1H), 7.88(d, 1H), 7.77(s, 2.84 1H), 7.61(s,1H), 7.59(s, 1H), 7.50(s, 1H), 6.48(s, 1H), 4.05(m, 2H), 3.10(m, 2H),2.08(s, 3H), 1.31(m, 6H) DMSO-d6 73 422.40 DMSOd6 12.3(bs, 1H); 9.3(s,1H); 8.8(s, 1H); 8.2(s, 1H); 3.20 7.5(dd, 1H); 7.2(d, 1H); 6.8(d, 1H);4.4(q, 2H); 4.3(bs, 4H); 3.1(bs, 2H); 2.1(s, 3H); 1.3(t, 3H); 1.2(bs,6H) 74 450.40 DMSOd6 12.3(bs, 1H); 9.4(s, 1H); 8.9(s, 1H); 8.2(s, 1H);3.70 7.7(dd, 1H); 7.2(d, 1H); 6.8(d, 1H); 4.4(bd, 4H); 4.1(d, 2H);3.1(bs, 2H); 2.1(s, 3H); 2.05(m, 1H); 1.3(bs, 6H); 1.0(d, 6H) 75 429.00good 3.70 76 399.00 good 3.17 77 366.30 MeOD4 8.4(s, 1H); 8.1(s, 1H);7.9(s, 1H); 7.6(dd, 1H); 2.10 7.2(d, 1H); 6.8(d, 1H); 4.3(bs, 4H);3.2(bs, 2H); 2.2(s, 3H); 1.3(bs, 6H) 78 429.00 79 423.00 80 423.00 81399.00 12.43(s, 1H), 8.48(s, 1H), 8.33(d, 1H), 8.06(d, 1H), 2.21 7.59(d,1H), 6.87(d, 1H), 4.7-6.3(m, 4H), 4.2-4.6(m, 1H), 4.20(m, 2H), 3.05(m,2H), 2.06(s, 3H), 1.25(m, 6H) DMSO-d6 82 368.50 DMSO d6 12.3(s, 1H);8.9(s, 1H); 8.2(s, 1H); 7.6(s, 1H); 2.10 7.2(s, 1H); 6.7(s, 1H); 4.4(d,1H); 3.7-4.1(m, 5H); 2.9(s, 3H); 1.9-2.4(m, 5H); 1.6(s, 1H) 83 386.40DMSO d6 12.2ppm (s, 1H), 8.7(s, 1H), 8.26(s, 1H), 8.23(s, 3.10 1H),7.5(t, 1H), 7.1(d, 1H), 6.5(d, 1H), 3.8(m, 2H), 3.75(t, 2H), 3.6(m, 2H),3.55(s, 1H), 3.45(s, 1H), 3.35(m, 2H), 1.9(m, 3H) 84 400.40 DMSO d612.2ppm (s, 1H), 8.7(s, 1H), 8.26(s, 1H), 8.23 3.30(s, 1H), 7.5(t, 1H),7.1(d, 1H), 6.5(d, 1H), 4.0(m, 1H), 3.9(m, 1H), 3.8(m, 2H), 3.75(m, 2H),3.65(m, 2H), 3.35(m, 2H), 1.9(m, 2H), 1.0(dt, 3H) 85 369.90 DMSO-D6:12.2(1H, s); 8.7(1H, s); 8.25(2H, m); 7.6(1H, 2.62 dd); 7.25(1H, d);6.7(1H, d); 3.8-3.5(8H, m); 2.4(2H, q); 1.05(3H, t). 86 384.00 DMSO-D6:12.2(1H, s); 8.7(1H, s); 8.25(2H, m); 7.6(1H, 2.86 dd); 7.25(1H, d);6.7(1H, d); 3.8-3.5(8H, m); 2.4(2H, q); 1.55(2H, sextet); 0.95(3H, t).87 302.90 DMSO d6: 12.2(s, 1H), 10.3(s, 1H), 9.3(d, 1H), 8.3(d, 3.201H), 8.2(d, 1H), 7.7(t, 1H), 7.6(m, 2H), 3.7(s, 3H) 88 330.90 DMSO d6:12.2(s, 1H), 10.3(s, 1H), 9.3(s, 1H), 8.35(s, 3.90 1H), 8.25(s, 1H),7.7(t, 1H), 7.6(d, 1H), 7.55(d, 1H), 4.1(t, 2H), 1.7(m, 2H), 2 0(t, 3H)89 398.00 DMSO-D6: 12.2(1H, s); 8.7(1H, s); 8.25(2H, m); 7.6(1H, 3.08dd); 7.2(1H, d); 6.7(1H, d); 3.6-3.3(8H, m); 2.3(2H, d); 2.0(1H, m);0.9(6H, d). 90 344.80 DMSO d6: 12.2ppm (s, 1H), 10.3(s, 1H), 9.3(s, 1H),8.3(s, 4.20 1H), 8.25(s, 1H), 7.7(t, 1H), 7.6(d, 1H), 7.55(d, 1H),3.95(d, 2H), 2.0(m, 1H), 1.0(d, 6H) 91 378.80 DMSO d6: 12.2ppm (s, 1H),10.4(s, 1H), 9.3(s, 1H), 8.3(s, 4.20 1H), 8.2(s, 1H), 7.7(t, 1H),7.62(d, 1H), 7.57(d, 1H), 7.5(m, 2H), 7.4(m, 2H), 5.2(s, 2H) 92 409.0012.56(s, 1H), 8.73(d, 1H), 8.52(d, 1H), 8.32(d, 1H), 8.05(d, 2.95 1H),7.52(d, 1H), 4.0-4.7(m, 4H), 3.24(m, 2H), 2.09(s, 3H), 1.36(m, 6H)DMSO-d6 93 409.00 12.54(s, 1H), 8.57(d, 1H), 8.36(d, 1H), 8.33(d, 1H),7.93(d, 2.82 1H), 6.92(d, 1H), 4.0-4.6(m, 4H), 3.2(M, 2H), 2.05(s, 3H),1.24(m, 6H) DMSO-d6 94 437.00 DMSO d6 8.2(s, 1H); 8.1(s, 1H); 8.0(s,1H); 7.6(dd, 1H); 1.59 7.1(d, 1H); 6.8(d, 1H); 4.5(t, 2H); 4.4(bs, 2H);4.3(d, 2H); 3.7(bs, 2H); 3.1(bs, 2H); 3.0(s, 6H); 2.0(s, 3H); 1.2(bs,6H) 95 479.00 DMSO d6 8.2(s, 1H); 8.1(s, 1H); 7.9(s, 1H); 7.5(dd, 1H);1.63 7.0(d, 1H); 6.6(d, 1H); 4.7(t, 2H); 4.4(d, 2H); 4.0-3.8(bs, 6H);3.8(t, 2H); 3.7-3.5(bs, 4H); 3.1(bs, 2H); 3.0(s, 6H); 2.0(s, 3H);1.2(bs, 6H) 96 436.00 DMSO d6 8.2(s, 1H); 8.1(s, 1H); 7.9(s, 1H);7.5(dd, 1H); 2.25 7.0(d, 1H); 6.6(d, 1H); 4.7(t, 2H); 4.4(d, 2H);4.0-3.8(bs, 6H); 3.8(t, 2H); 3.7-3.5(bs, 4H); 3.1(bs, 2H); 3.0(s, 6H);2.0(s, 3H); 1.2(bs, 6H) 97 427.00 12.29(s, 1H), 8.73(d, 1H), 8.30(m,2H), 8.09(s, 1H), 7.59(s, 2.35 1H), 7.52(s, 1H), 7.06(s, 1H), 4.1-4.8(m,4H), 3.1(m, 2H), 2.09(s, 3H), 1.25(m, 6H) DMSO-d6 98 409.00 12.39(s,1H), 8.70(d, 1H), 8.43(d, 1H), 8.31(s, 1H), 7.52(s, 3.04 1H), 7.17(s,1H), 4.39(m, 4H), 3.15(m, 2H), 2.09(s, 3H), 1.25(m, 6H) DMSO-d6 99300.90 CDCl3: 10.3(s, 1H); 9.7(s, 1H); 8.3(s, 1H); 8.1(s, 1H); 2.017.9(s, 1H); 7.7(dd, 1H); 6.8(d, 1H); 6.5(d, 1H); 3.05(d, 2H); 2.0(m,1H); 1.0(d 6H). 100 364.90 DMSO-D6: 12.3(br s, 1H); 8.6(s, 1H); 8.3(s,1H); 8.2(s, 1.99 1H); 7.5(m, 3H); 7.3(m, 2H); 7.2(m 1H); 7.1(m, 1H);6.5(brs, 1H); 5.05(br s 1H); 3.75(m, 1H); 3.7(m, 1H). 101 364.90 CDCl3:10.6(br s, 1H); 10.25(br s, 1H); 8.3(s, 1H); 8.1(s, 1.98 1H); 7.9(s,1H); 7.6(dd, 1H); 7.3(m, 6H); 6.8(d, 1H); 6.25(d, 1H); 4.6(m, 1H);3.95(m, 1H); 3.9(m, 1H). 102 302.90 DMSO-D6(~2:1 rotationalmixture):12.6(br s, 1H); 12.2(brs, 1.62 1H); 8.7(s, .33H); 8.6(s, .67H); 8.3(s,.67H); 8.25(s, 1H); 8.2(s, .33H); 7.8(s, .67H); 7.5(s, .33H); 7.15(d,.67H); 7.05(d, .33H); 6.8(s, .67H); 6.45(s, .33H); 4.5(m, 1H); 4.1(m,1H); 3.6(m, 2H); 1.3(d, .6H); 1.2(d, 2.4H). 103 302.90 DMSO-D6(~2:1rotational mixture): 12.65(br s, 1H); 1.63 12.25(br s, 1H); 8.7(s, .4H);8.6(s, .6H); 8.35(s, .67H); 8.3(s, 1H); 8.25(s, .33H); 7.8(s, .67H);7.5(s, .33H); 7.2(d, .67H); 7.1(d, .33H); 6.8(s, .67H); 6.5(s, .33H);4.5(m, 1H); 4.05(m, 1H); 3.5(m, 2H); 1.3(d, .6H); 1.2(d, 2.4H). 104272.80 DMSO d6 12.3(s, 1H); 8.4(s, 1H); 8.3(s, 1H); 8.1(s, 1H); 2.618.0(d, 1H); 7.8(d, 1H). 105 271.90 DMSO d6 12.2(s, 1H); 8.4(s, 1H);8.3(s, 1H); 8.1(s, 1H); 2.26 7.9(d, 1H); 7.8(d, 1H). 106 273.80 DMSO d612.4(s, 1H); 9.2(s, 1H); 8.9(s, 1H); 8.5(s, 1H); 2.34 8.3(s, 1H); 8.2(d,1H); 8.0(d, 1H). 107 272.90 DMSO d6 12.3(s, 1H); 9.1(s, 1H); 8.9(s, 1H);8.5(s, 1H); 2.01 8.3(s, 1H); 8.1(d, 1H); 8.0(bs, 1H); 7.9(d, 1H);7.5(bs, 1H). 108 506.00 DMSO-d6: 12.2(s, 1H); 9.6(br s, 1H); 9.25(s,1H); 8.8(s, 1.59 1H); 8.25(s, 1H); 7.6(dd, 1H); 7.2(d, 1H); 6.7(d, 1H);4.4(brs, 4H); 4.0(m, 2H); 3.8-3.6(m, 6H); 3.35(m, 2H); 3.2(brs, 2H);3.1(br s, 2H); 2.1(s, 3H); 1.3(s, 6H). 109 533.00 DMSO-d6: 12.2(s, 1H);9.2(s, 1H); 8.75(s, 1H); 8.6(br s, 1.46 1H); 8.2(s, 1H); 7.6(dd, 1H);7.2(d, 1H); 6.75(d, 1H); 4.4(brs, 4H); 3.6-2.7(m, 17H); 2.1(s, 3H);1.9(m, 2H); 1.3(s, 6H). 110 452.00 12.09(s, 1H), 8.28(d, 1H), 8.20(d,1H), 7.77(d, 1H), 7.11(d, 2.31 1H), 6.97(d, 1H), 4.0-4.7(m, 4H), 3.30(s,8H), 3.18(m, 2H), 2.10(s, 3H), 1.28(m, 6H) DMSO-d6 111 452.00 12.32(s,1H), 8.76(d, 1H), 8.37(d, 1H), 8.31(d, 1H), 7.71(s, 2.59 1H), 7.27(s,1H), 4.0-4.7(m, 4H), 3.30(s, 6H), 3.20(m, 2H), 2.09(s, 3H), 1.29(m, 6H)DMSO-d6 112 366.00 DMSOd6 12.2(bs, 1H); 8.2(s, 1H); 8.1(s, 1H); 8.0(s,1H); 1.90 7.6(dd, 1H); 7.1(dd, 1H); 6.5(dd, 1H); 4.0(m, 1H); 3.9(s, 3H);3.8(m, 2H); 3.75(m, 1H); 3.7(m, 2H); 3.5(m, 2H); 2.0(s, 3H); 1.9(m, 2H)113 407.00 DMSO d6: 11.8ppm (s, 1H), 10(s, 1H), 9.2(s, 1H), 8.2(s, 2.101H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.05(m,2H), 2.1(s, 3H), 2.08(s, 3H), 1.3(bs, 6H) 114 421.00 DMSO d6: 11.8ppm(s, 1H), 9.9(s, 1H), 9.3(s, 1H), 8.2(s, 2.20 1H), 8.1(s, 1H), 7.5(t,1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.0(m, 2H), 2.4(m, 2H), 2.1(s,3H), 1.3(bs, 6H), 1.1(t, 3H) 115 491.00 DMSO d6: 11.9ppm (s, 1H), 10(s,1H), 9.3(s, 1H), 8.6(bs, 1.50 1H), 8.2(s, 1H), 8.15(s, 1H), 7.5(t, 1H),7.1(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.4(bs, 2H), 3.2(bs, 4H), 3.0(m,2H), 2.9(bs, 4H), 2.1(s, 3H), 1.3(bs, 6H) 116 492.00 DMSO d6: 12ppm (s,1H), 10.7(bs, 1H), 9.3(s, 1H), 8.22(s, 1.60 1H), 8.19(s, 1H), 7.5(t,1H), 7.2(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 4.2(bs, 2H), 3.8(t, 4H), 3.1(m,4H), 3.0(m, 2H), 2.1(s, 3H), 1.3(bs, 6H) 117 435.00 DMSO d6: 11.8ppm (s,1H), 9.9(s, 1H), 9.3(s, 1H), 8.2(s, 2.40 1H), 8.1(s, 1H), 7.5(t, 1H),7.1(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.0(m, 2H), 2.6(m, 1H), 2.1(s, 3H),1.3(bs, 6H), 1.1(d, 6H) 118 419.00 DMSO d6: 11.9ppm (s, 1H), 10.2(s,1H), 9.4(s, 1H), 8.2(s, 2.30 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H),6.7(d, 1H), 6.5(m, 1H), 6.3(d, 1H), 5.8(d, 1H), 4.4(m, 4H), 3.0(m, 2H),2.1(s, 3H), 1.3(bs, 6H) 119 493.00 DMSO d6: 11.8ppm (s, 1H), 10.0(s,1H), 9.3(s, 1H), 8.2(s, 2.50 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H),6.7(d, 1H), 4.4(m, 4H), 4.0(m, 4H), 3.0(m, 2H), 2.6(m, 2H), 2.1(s, 3H),1.3(bs, 6H), 1.2(t, 3H) 120 452.00 8.79(d, 1H), 8.46(s, 1H), 8.26(d,1H), 8.07(s, 1H), 7.69(d, 2.43 1H), 7.40(d, 1H), 5.71(s, 2H), 4.91(s,2H), 4.20(s, 2H), 3.70(s, 4H), 3.40(m, 2H), 3.25(s, 1H), 3.12(s, 1H),3.03(s, 1H), 2.95(m, 2H), 1.99(s, 3H), 1.09(m, 6H) CD3CN with 4 drops ofDMSO-d6 121 506.30 DMSO d6: 11.9ppm (s, 1H), 10.3(S, 1H), 9.3(S, 1H),8.2(s, 1.70 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(m,4H), 4.0(d, 2H), 3.7(t, 2H), 3.5(m, 4H), 3.1(m, 4H), 3.0(t, 2H), 2.1(s,3H), 1.3(bs, 6H) 122 272.90 DMSO-d6: 12.2(br s, 1H); 8.8(s, 1H); 8.25(m,2H); 7.55(dd, 2.05 1H); 7.1(d, 1H); 6.5(d, 1H); 3.1(s, 6H). 123 315.00DMSO-d6: 12.2(br s, 1H); 8.8(s, 1H); 8.25(m, 2H); 7.5(dd, 3.55 1H);7.1(d, 1H); 6.45(m, 1H); 3.5(d, 2H); 3.1(s, 3H); 2.15(m, 1H); 0.95(d,6H). 124 492.00 DMSO-d6: 12.2(br s, 1H); 9.7(br s, 1H); 9.2(m, 1H);8.8(s, 2.24 1H); 8.2(s, 1H); 7.5(m, 1H); 7.1(m, 1H); 6.5(m, 1H);4.1-3.5(m, 14H); 3.4(m, 4H); 3.2(br s, 2H); 2.0-1.8(m, 5H). 125 519.10DMSO-d6: 12.2(br s, 1H); 9.2(d, 1H); 8.8(s, 1H); 8.65(br 1.75 s, 1H);8.2(s, 1H); 7.5(m, 1H); 7.1(m, 1H); 6.5(dd, 1H); 4.1-3.1(m, 18H); 3.0(brs, 4H); 2.8(s, 3H); 2.0-1.8(m, 5H). 126 379.90 DMSO-d6: 11.8(br s, 1H);9.2(s, 1H); 8.8(s, 1H); 8.0(s, 1.83 1H); 7.5(dd, 1H); 7.1(d, 1H);6.5(dd, 1H); 4.0(m, 1H); 3.8-3.65(m, 5H); 3.4(m, 2H); 2.0-1.8(m, 5H).127 477.90 DMSO d6: 11.8ppm (s, 1H), 9.0(s, 1H), 8.6(s, 1H), 8.2(s, 2.101H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.3(m, 4H), 3.6(t,4H), 3.5(t, 4H), 3.0(m, 2H), 2.1(s, 3H), 1.2(bs, 6H) 128 505.00 DMSO d6:11.9ppm (s, 1H), 10.3(s, 1H), 9.3(s, 1H), 8.2(s, 1.50 1H), 8.1(s, 1H),7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.3(m, 12H), 3.0(m, 2H),2.8(m, 2H), 2.1(3H), 1.3(bs, 6H) 129 355.10 MeOD-D4: 8.4(s, 1H); 8.35(s,1H); 8.1(s, 1H); 8.0(dd, 2.40 1H); 7.2(d, 1H); 7.0(d, 1H); 3.75(m, 1H);1.9-1.8(m, 3H); 1.7(m, 1H); 1.55(m, 1H); 1.3-1.1(m, 9H). 130 315.10MeOD-D4: 8.4(s, 1H); 8.35(s, 1H); 8.15(s, 1H); 8.0(dd, 2.00 1H); 7.2(d,1H); 7.0(d, 1H); 3.8(m, 1H); 1.9(m, 1H); 1.3(d, 3H); 1.0(m, 6H). 131367.00 MeOD-D4: 8.3(m, 2H); 8.1(s, 1H); 7.9(dd, 1H); 7.5(m, 2.40 2H);7.2(d, 1H); 7.1(m, 2H); 6.75(d, 1H); 5.0(m, 1H); 1.65(d, 3H). 132 342.80DMSO-D6: 12.5(br s, 1H); 8.7(br s, 1H); 8.35-8.15(m, 2.00 2H); 7.7(br s,1H); 7.1(m, 1H); 6.8(br s, 1H); 3.8(br s, 1H); 3.7-3.5(m, 2H); 2.0(m,1H); 1.25-0.8(m, 8H). 133 360.90 DMSO-D6: 12.3(br s, 1H); 8.8(br s, 1H);8.25(m, 2H); 7.6(brs, 3.00 1H); 7.4-7.1(m, 5H); 6.5(br s, 1H); 5.6(br s,1H); 3.0(m, 1H); 2.9(m, 1H); 2.6(m, 1H); 1.95(m, 1H). 134 330.80DMSO-D6: 12.5(br s, 1H); 8.7(br s, 1H); 8.3-8.25(m, 2.00 2H); 7.6(br s,1H); 7.2(br s, 1H); 6.7(br s, 1H); 3.8(br s, 1H); 3.65-3.5(m, 3H);2.0(m, 1H); 1.0(m, 7H). 135 330.80 DMSO-D6: 12.5(br s, 1H); 8.6(br s,1H); 8.3-8.2(m, 2H); 2.00 7.7(br s, 1H); 7.1(br s, 1H); 6.8(br s, 1H);3.8(br s, 1H); 3.7-3.5(m, 3H); 2.0(m, 1H); 1.0(m, 7H). 136 376.90DMSO-D6: 12.5(br s, 1H); 8.7(br s, 1H); 8.3(m, 2H); 7.4-7.1(m, 2.40 5H);5.5(br s, 1H); 4.7(m, 1H); 3.2(m, 1H); 2.9(m, 1H). 137 376.90 DMSO-D6:12.1(br s, 1H); 8.8(br s, 1H); 8.2(m, 2H); 2.40 7.45-7.05(m, 5H);6.5-6.4(m, 2H); 5.5(br s, 1H); 4.7(m, 1H); 3.15(m, 1H); 2.9(m, 1H). 138430.00 DMSO-d6 11.9ppm (s, 1H), 10.2(s, 1H), 9.3(s, 1H), 8.3(s, 2.301H), 8.1(s, 1H), 7.5(m, 1H), 7.1(m, 1H), 6.5(m, 2H), 6.3(d, 1H), 5.8(d,1H), 3.5-4.0(m, 10H), 1.9(m, 2H) 139 405.10 DMSO-d6 11.9ppm (s, 1H),10.2(s, 1H), 9.3(s, 1H), 8.3(s, 2.00 1H), 8.1(s, 1H), 7.5(m, 1H), 7.1(m,1H), 6.5(m, 2H), 6.3(s, 1H), 5.8(s, 1H), 4.0(t, 1H), 3.8(dt, 2H, 3.7(m,3H), 3.4(m, 2H), 2.0(s, 1H), 1.9(t, 1H), 1.8(s, 3H) 140 393.10 DMSO-d611.9ppm (s, 1H), 10.0(s, 1H), 9.1(s, 1H), 8.2(s, 1.70 1H), 8.1(s, 1H),7.5(m, 1H), 7.1(m, 1H), 6.5(m, 2H), 4.0(t, 1H), 3.8(dt, 2H), 3.7(m, 3H),3.4(m, 2H), 2.1(s, 3H), 2.0(s, 1H), 1.9(t, 1H), 1.8(s, 3H) 141 407.00DMSO-d6 11.8ppm (s, 1H), 9.9(s, 1H), 9.1(s, 1H), 8.2(s, 1.90 1H), 8.1(s,1H), 7.5(m, 1H), 7.1(m, 1H), 6.5(m, 2H), 4.0(t, 1H), 3.8(dt, 2H); 3.7(m,3H), 3.4(m, 2H), 2.4(q, 2H), 2.0(s, 1H), 1.9(t, 1H), 1.8(s, 3H), 1.1(t,3H) 142 334.80 DMSOD6 12.2(bs, 1H); 8.3(s, 1H); 8.15(s, 1H); 8.0(s, 4.601H); 7.6(d, 2H); 7.5(dd, 2H); 7.4(dd, 2H); 7.3(d, 2H); 6.95(d, 1H);5.1(s, 2H) 143 287.80 DMSO D6 12.1(bs, 1H); 8.3(s, 2H); 7.9(s, 1H);7.55(d, 4.60 1H); 7.4(dd, 2H); 7.2(d, 1H); 2.95(hept, 1H); 1.25(d, 6H)144 271.90 DMSO D6 12.1(bs, 1H); 8.3(s, 2H); 7.9(s, 1H); 7.3(d, 2.601H); 7.2(bs, 2H); 6.8(app d, 1H); 2.9(s, 6H) 145 333.80 4.10 146 382.90DMSO d6 12.1(bs, 1H); 8.3(s, 1H); 8.25(s, 1H); 8.0(s, 3.70 1H); 7.3(dd,1H); 7.2(m, 2H); 6.9(s, 1H); 4.2(bs, 2H); 3.6(d, 2H); 2.8(bs, 2H);2.0(s, 3H); 1.3(bs, 6H) 147 378.10 3.00 148 288.10 2.00 149 395.10DMSO-D6: 12.4(s, 1H); 8.7(d, 1H); 8.4(s, 1H); 8.25(s, 3.30 1H), 7.5(s,1H); 6.9(d, 1H); 4.0-3.65(m, 6H); 3.4(m, 2H); 2.0-1.8(m, 5H). 150 326.00DMSO-D6: 12.3(s, 1H); 8.9(s, 1H); 8.4(s, 1H); 8.25(s, 3.70 1H), 7.35(s,1H); 7.25(m, 1H); 6.6(s, 1H); 3.2(m, 2H); 2.0(m, 1H); 1.0(d, 6H). 151353.00 DMSO-D6: 12.4(s, 1H); 8.75(br s, 1H)8.7(s, 1H); 8.45(s, 1.80 1H);8.3(s, 1H), 7.6(s, 1H); 7.0(s, 1H); 4.0(m, 2H); 3.8(m, 2H); 3.35(m, 2H);3.2(m, 2H); 2.1(m, 2H). 152 519.20 DMSO d6: 11.9ppm (s, 1H), 10.1(s,1H), 9.3(s, 1H), 9.0(bs, 1.40 1H), 8.2(s, 1H), 8.1(s, 1H), 7.5(t, 1H),7.15(d, 1H), 6.7(d, 1H), 4.3(m, 4H), 3.0-3.8(m, 14H), 3.1(m, 2H), 2.1(s,3H), 2.0(q, 2H), 1.3(bs, 6H) 153 520.20 DMSO d6: 11.9ppm (s, 1H),10.1(s, 1H), 9.3(s, 1H), 8.2(s, 1.60 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d,1H), 6.7(d, 1H), 4.3(m, 4H), 4.0(d, 2H), 3.7(t, 4H), 3.5(d, 2H), 3.2(m,2H), 3.1(m, 4H), 2.1(s, 3H), 2.0(q, 2H), 1.3(bs, 6H) 154 433.10 DMSO d6:11.9ppm (s, 1H), 9.9(s, 1H), 9.3(s, 1H), 8.3(s, 2.20 1H), 8.1(s, 1H),7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 5.9(s, 1H), 5.5(s, 1H), 4.4(m, 4H),3.0(m, 2H), 2.1(s, 3H), 2.0(s, 3H), 1.3(bs, 6H) 155 473.10 DMSO d6:11.8ppm (s, 1H), 9.6(s, 1H), 9.3(s, 1H), 8.3(s, 2.60 1H), 8.1(s, 1H),7.5(t, 1H), 7.1(d, 1H), 6.75(t, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.0(m, 2H),2.3(m, 2H), 2.2(m, 2H), 2.1(s, 3H), 1.7(m, 2H), 1.6(m, 2H), 1.3(bs, 6H)156 469.10 DMSO d6: 11.9ppm (s, 1H), 10.3(s, 1H), 9.4(s, 1H), 8.4(s,2.50 1H), 8.1(s, 1H), 8.0(d, 2H), 7.6(m, 4H), 7.2(d, 1H), 6.7(d, 1H),4.4(m, 4H), 3.1(m, 2H), 2.1(s, 3H), 1.3(bs, 6H) 157 459.10 DMSO d6:11.9ppm (s, 1H), 9.7(s, 1H), 9.3(s, 1H), 8.3(s, 2.40 1H), 8.1(s, 1H),7.5(t, 1H), 7.1(d, 1H), 6.75(s, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.1(m, 2H),2.6(dt, 4H), 2.1(s, 3H), 1.9(q, 2H), 1.3(bs, 6H) 158 475.20 DMSO d6:11.8ppm (s, 1H), 9.8(s, 1H), 9.3(s, 1H), 8.15(s, 2.60 1H), 8.1(s, 1H),7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.1(m, 2H), 2.4(m, 1H),2.1(s, 3H), 1.8(dd, 4H), 1.4(q, 2H), 1.3(bs, 10H) 159 379.00 12.03(s,1H), 8.7-9.8(s, 5H), 8.40(s, 1H), 8.08(s, 1H), 1.70 7.96(s, 1H), 7.77(t,1H), 7.15(d, 1H), 6.90(d, 1H), 4.15-4.7(m, 4H), 3.31(m, 2H), 2.95(s,3H), 2.16(s, 3H), 1.37(m, 6H) CD3CN 160 440.90 DMSO d6 12.3(bs, 1H);10.0(bs, 1H); 8.6(s, 1H); 8.2(s, 2.40 1H); 8.1(s, 1H); 7.3(s, 1H);7.1(s, 1H); 4.4(bs, 2H); 4.2(d, 2H); 3.1(bd, 2H); 2.05(s, 3H); 2.01(s,3H); 1.3(bs, 6H) 161 447.00 DMSO d6: 11.8ppm (s, 1H), 9.7(s, 1H), 9.3(s,1H), 8.3(s, 2.40 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H),6.5(q, 1H), 4.4(m, 4H), 3.1(m, 2H), 2.1(s, 3H), 1.9(s, 3H), 1.8(d, 3H),1.2(bs, 6H) 162 475.90 DMSO d6: 11.9ppm (s, 1H), 10.5(s, 1H), 9.4(s,1H), 9.3(s, 2.30 1H), 8.5(s, 1H), 8.45(s, 1H), 8.1(s, 1H), 7.6(t, 1H),7.1(d, 1H), 6.7(d, 1H), 4.3(m, 4H), 3.1(m, 2H), 2.1(s, 3H), 1.3(bs, 6H)163 470.00 DMSO d6: 11.9ppm (s, 1H), 10.6(s, 1H), 9.4(s, 1H), 9.3(s,2.10 1H), 9.2(s, 1H), 8.8(d, 1H), 8.4(s, 1H), 8.4(d, 1H), 8.2(s, 1H),7.7(q, 1H), 7.6(t, 1H), 7.2(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.1(m, 2H),2.1(s, 3H), 1.3(bs, 6H) 164 471.00 DMSO d6: 11.9ppm (s, 1H), 10.9(s,1H), 9.5(s, 1H), 9.3(s, 2.30 1H), 9.0(s, 1H), 8.8(s, 1H), 8.5(s, 1H),8.2(s, 1H), 7.6(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(m, 4H), 3.0(m, 2H),2.1(s, 3H), 1.3(bs, 6H) 165 433.00 DMSO d6: 11.8ppm (s, 1H), 10.2(s,1H), 9.3(s, 1H), 8.2(s, 2.30 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H),6.7(d, 1H), 4.3(bd, 4H), 3.0(bd, 2H), 2.1(s, 1H), 1.8(m, 1H), 1.3(bs,6H), 0.8(m, 4H) 166 461.10 DMSO d6: 11.8ppm (s, 1H), 9.9(s, 1H), 9.3(s,1H), 8.2(s, 2.60 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H),4.4(bd, 4H), 3.0(bd, 2H), 2.8(q, 1H), 2.1(s, 1H), 1.9(m, 1H) 1.8(m, 1H),1.7(m, 1H), 1.6(m, 1H), 1.3(bs, 6H) 167 460.00 DMSO d6: 12.0ppm (s, 1H),10.9(s, 1H), 9.3(s, 1H), 8.8(s, 2.30 1H), 8.4(s, 1H), 8.2(s, 1H), 7.6(t,1H), 7.2(s, 1H), 7.15(d, 1H), 6.7(d, 1H), 4.4(bd, 4H), 3.1(bd, 2H),2.1(s, 3H), 1.3(bs, 6H) 168 483.00 DMSO d6: 11.9ppm (s, 1H), 10.3(s,1H), 9.4(s, 1H), 8.4(s, 2.70 1H), 8.2(s, 1H), 7.85(s, 1H), 7.8(d, 1H),7.6(t, 1H), 7.4(s, 2H), 7.4(q, 1H), 7.2(d, 1H), 6.7(d, 1H), 4.4(bd, 4H),3.1(bd, 2H), 2.4(s, 3H), 2.1(s, 3H), 1.3(bs, 6H) 169 487.00 DMSO d6:11.9ppm (s, 1H), 10.4(s, 1H), 9.4(s, 1H), 8.4(s, 2.70 1H), 8.2(s, 1H),7.9(d, 1H), 7.8(d, 1H), 7.6(q, 1H), 7.55(t, 1H), 7.45(t, 1H), 7.2(d,1H), 6.7(d, 1H), 4.4(bd, 4H), 3.1(bd, 2H), 2.1(s, 3H), 1.3(bs, 6H) 170437.00 DMSO d6: 11.9ppm (s, 1H), 9.8(s, 1H), 9.3(s, 1H), 8.3(s, 2.101H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(bd, 4H), 4.1(s,2H), 3.4(s, 1H), 3.0(bd, 2H), 2.1(s, 3H), 1.3(bs, 6H) 171 476.00 DMSOd6: 12.0ppm (s, 1H), 10.5(s, 1H), 9.0(s, 1H), 8.3(s, 1.70 1H), 8.2(s,1H), 7.6(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(bd, 4H), 3.3(m, 2H),3.0(bd, 2H), 2.3(m, 2H), 2.1(s, 3H), 1.5-1.9(m, 4H), 1.3(bs, 6H) 172487.00 DMSO d6: 11.9ppm (s, 1H), 10.4(s, 1H), 9.4(s, 1H), 8.3(s, 2.601H), 8.2(s, 1H), 7.7(t, 1H), 7.6(q, 1H), 7.5(t, 1H), 7.4(q, 2H), 7.2(d,1H), 6.7(d, 1H), 4.4(bd, 4H), 3.1(bd, 2H), 2.1(s, 3H), 1.3(bs, 6H) 173502.90 DMSO d6: 11.9ppm (s, 1H), 10.5(s, 1H), 9.4(s, 1H), 8.3(s, 2.601H), 8.2(s, 1H), 7.4-7.7(m, 5H), 7.2(d, 1H), 6.7(d, 1H), 4.4(bd, 4H),3.1(bd, 2H), 2.0(s, 3H), 1.3(bs, 6H) 174 502.90 DMSO d6: 11.9ppm (s,1H), 10.5(s, 1H), 9.4(s, 1H), 8.4(s, 2.90 1H), 8.2(s, 1H), 8.0(d, 1H),7.7(s, 1H), 7.6(t, 1H), 7.5(t, 1H), 7.2(d, 1H), 6.7(d, 1H), 4.4(bd, 4H),3.1(bd, 2H), 2.1(s, 3H), 1.3(bs, 6H) 175 307.00 DMSO d6 12.4(bs, 1H);8.4(s, 1H); 8.3(s, 1H); 8.2(s, 2.80 1H); 7.95(d, 2H); 7.9(s, 1H) 176253.70 DMSO d6 12.4(bs, 1H); 8.5(s, 1H); 8.3(s, 1H); 8.2(s, 3.10 1H);8.0(d, 2H); 7.9(d, 2H) 177 350.95 DMSO d6 12.4(bs, 1H); 8.35(s, 1H);8.3(s, 1H); 8.2(m, 3.16 2H); 8.1(s, 1H); 7.9(s, 1H) 178 287.01 DMSO d612.2(bs, 1H); 8.4(s, 1H); 8.3(s, 1H); 8.0(s, 2.69 1H); 7.65(s, 1H);7.6(dd, 1H); 7.4(dd, 1H); 7.2(dd, 1H); 3.8(S, 2H) 179 494.00 DMSO d6:11.9ppm (s, 1H), 10.5(s, 1H), 9.4(s, 1H), 8.45(s, 2.60 1H), 8.4(s, 1H),8.3(d, 1H), 8.2(s, 1H),(8.1(d, 1H), 7.8(t, 1H), 7.6(t, 1H), 7.2(d, 1H),6.7(d, 1H), 4.4(bd, 4H), 3.1(bd, 2H), 2.1(s, 3H), 1.3(bs, 6H) 180 449.10DMSO d6: 11.8ppm (s, 1H), 9.9(s, 1H), 9.3(s, 1H), 8.2(s, 2.50 1H),8.1(s, 1H), 7.6(t, 1H), 7.1(d, 1H), 6.7(d, 1H), 4.4(bd, 4H), 3.1(bd,2H), 2.4(m, 1H), 2.1(s, 3H), 1.6(m, 1H), 1.4(m, 1H), 1.3(bs, 6H), 1.1(d,3H), 0.9(t, 3H) 181 433.00 DMSO d6: 11.9ppm (s, 1H), 10.0(s, 1H), 9.3(s,1H), 8.2(s, 2.30 1H), 8.1(s, 1H), 7.5(t, 1H), 7.1(d, 1H), 6.8(m, 1H),6.7(d, 1H), 6.2(d, 1H), 4.4(bd, 4H), 3.1(bd, 2H), 2.1(s, 3H), 1.9(d,3H), 1.3(bs, 6H) 182 474.90 DMSO d6: 11.9ppm (s, 1H), 10.3(s, 1H),9.3(s, 1H), 8.4(s, 2.50 1H), 8.2(s, 1H), 8.0(d, 1H), 7.9(d, 1H), 7.6(t,1H), 7.25(t, 1H), 7.2(d, 1H), 6.7(d, 1H), 4.4(bd, 4H), 3.1(bd, 2H),2.1(s, 3H), 1.3(bs, 6H) 183 228.80 DMSO d6 12.2(bs, 1H); 8.3(s, 1H);8.25(s, 1H); 8.0(s, 3.40 1H); 7.7(d, 2H); 7.4(dd); 7.2(dd, 1H) 184230.10 DMSO d6 12.2(bs, 1H); 8.3(s, 1H); 8.25(s, 1H); 8.0(s, 1.60 1H);7.7(d, 2H); 7.4(dd); 7.2(dd, 1H) 185 243.10 DMSO d6 12.2(bs, 1H); 8.3(s,1H); 8.25(s, 1H); 7.9(s, 3.40 1H); 7.5(dd, 2H); 7.3(dd, 1H); 7.1(d, 1H);2.3(s, 3H) 186 334.10 DMSO d6 12.2(bs, 1H); 8.25(s, 1H); 8.2(s, 1H);8.0(s, 2.60 1H); 7.5(d, 1H); 7.4(dd, 2H); 7.3(d, 1H); 7.05(dd, 2H);6.7(d, 2H); 6.55(dd, 1H); 4.3(s, 2H) 187 401.80 DMSO d6 12.2(bs, 1H);8.3(s, 1H); 8.05(s, 1H); 8.0(s, 3.90 1H); 7.5(m, 5H); 7.3(dd, 1H);7.2(s, 1H); 7.1(s, 1H); 6.8(s, 1H); 4.4(s, 2H) 188 291.02 2.30 189487.00 DMSO d6: 11.9ppm (s, 1H), 10.3(s, 1H), 9.3(s, 1H), 8.4(s, 2 601H), 8.15(s, 1H), 8.1(m, 2H), 7.5(t, 1H), 7.4(t, 2H), 7.15(d, 1H),6.7(d, 1H), 4.4(bd, 4H), 3.1(bd, 2H), 2.1(s, 3H), 1.3(bs, 6H) 190 460.00DMSO d6: 11.9ppm (s, 1H), 10.6(bs, 1H), 9.3(s, 1H), 8.5(s, 2.00 1H),8.2(s, 1H), 7.5(t, 1H), 7.1(d. 1H), 6.7(d, 1H), 4.4(bd, 4H), 3.1(bd,2H), 2.1(s, 3H), 1.2(bs, 6H) 191 445.00 DMSO d6: 11.9ppm (s, 1H),10.2(bs, 1H), 9.4(s, 1H), 8.3(s, 2.40 1H), 8.1(s, 1H), 7.5(t, 1H),7.2(m, 1H), 7.1(d. 1H), 6.7(d, 1H), 6.6(m, 1H), 6.3(d, 1H), 5.7(d, 1H),5.5(d, 1H), 4.4(bd, 4H), 3.1(bd, 2H), 2.1(s, 3H), 1.2(bs, 6H) 192 452.90DMSO d6: 11.9ppm (s, 1H), 10.3(s, 1H), 9.3(s, 1H), 8.2(s, 2.50 1H),8.1(s, 1H), 7.5(t, 1H), 7.4(d, 1H), 7.1(d. 1H), 6.7(d, 1H), 6.7(s, 1H),4.4(bd, 4H), 3.1(bd, 2H), 2.1(s, 3H), 1.2(bs, 6H) 193 456.10 DMSO-d6:11.9(bs, 1H); 8.3(s, 1H); 8.1(m, 2H); 7.55(dd, 3.00 1H); 7.45(d, 2H);7.4(dd, 2H); 7.3(m, 1H); 7.15(d, 1H); 6.7(d, 1H); 5.2(s, 2H); 4.2(d,4H); 3.1(m, 2H); 2.05(s, 3H); 1.25(s, 6H). 194 451.20 DMSO-d6: 11.9(bs,1H); 8.25(s, 1H); 8.1(s, 1H); 8.05(s, 1.60 1H); 7.55(dd, 1H); 7.15(d,1H); 6.7(d, 1H); 4.3(d, 4H); 4.15(m, 2H); 3.25(m, 2H); 3.05(m, 2H);2.8(s, 6H); 2.15(m, 2H); 2.05(s, 3H); 1.25(s, 6H). 195 279.80(d4-methanol, free base) 8.87(s, 1H), 8.70(s, 1H), 8.50(s, 2.86 1H),8.38(s, 1H), 8.20(d, 1H), 8.18(d, 1H), 8.10(m, 1H), 7.96(m, 1H) 196311.80 (d4-methanol, salt) 8.88(s, 1H), 8.25(m, 2H), 7.86(s, 1H), 3.957.34(m, 1H), 2.72(s, 3H) 197 293.80 (d4-methanol, salt) 8.71-7.45(m,8H), 2.90(s, 3H) 2.33 198 293.90 (d4-methanol, salt) 8.53-7.82(m, 7H),7.41(s, 1H), 4.34(s, 2.33 3H) 199 278.90 (d4-methanol, salt) 8.39(dd,1H), 8.25(s, 1H), 8.11(s, 1H), 3.87 7.94-7.79(m, 5H), 7.51-7.44(m, 2H)200 279.90 (d4-methanol, salt) 9.16-7.99(m, 9H) 3.87 201 259.90(d4-methanol, salt) 8.86(d, 1H), 8.23(s, 1H), 8.09(s, 1H), 3.46 7.99(m,1H), 7.70(d, 1H), 7.39(dd, 1H), 6.65(d, 1H), 4.17(s, 3H) 202 279.80(d4-methanol, salt) 9.01(d, 1H), 8.98(d, 1H), 8.32(s, 1H), 2.50 8.31(s,1H), 8.28(d, 1H), 8.17(d, 1H), 8.01-7.97(m, 2H), 7.94(s, 1H) 203 287.90(CDCl3) 10.00(br s, 1H), 8.49(s, 1H), 8.27(s, 1H), 8.00s, 2.56 1H),7.71(m, 1H), 7.48(m, 1H), 7.20(m, 1H), 7.19(d, 1H), 1.97(s, OH, 1H),1.57(s, 6H) 204 412.90 DMSO d6 12.2(bs, 1H); 8.7(t, 1H); 8.4(s, 1H);8.2(s, 1.90 1H); 8.1(s, 1H); 8.0(s, 1H); 4.8(q, 1H); 3.9(s, 3H); 3.85(m,2H); 1.15(d, 3H) 205 394.20 2.10 206 408.10 2.20 207 420.20 2.30 208493.20 1.70 209 452.20 2.20 210 343.00 1H NMR (CDCl3) 0.30(9H, s),7.33-7.54(8H, m), 7.59-7.68(2H, m), 8.05-8.08(1H, m), 8.61-8.65(1H, m),9.70(1H, brs). 211 349.10 (400MHz, DMSO-d6) 7.30-7.43(8H, brm), 7.48(2H,m), 7.98(1H, d), 8.34(1H, d), 12.36(1H, brm). 212 364.40 (400MHz,DMSO-d6) 7.00(2H, d), 7.23(2H, d), 7.34(3H, m), 7.49(2H, dd), 7.97(1H,s), 8.33(1H, d) and 12.38(1H, s). 213 271.00 1H NMR (CDCl3)7.30-7.57(6H, m), 7.60-7.77(5H, m), 8.44-8.48(1H, m), 8.65-8.70(1H, m),11.21(1H, brs). 214 301.00 1H NMR (DMSO) 3.84(3H, s), 6.80-6.88 91H, m),7.25-7.30(1H, m), 7.32-7.41(3H, m), 7.45-7.54(2H, m), 7.72-7.81(2H, m),7.90-7.98(1H, m), 8.39-8.43 91H, m), 8.54-8.60(1H, m), 12.04(1H, brs).215 315.00 1H NMR (DMSO) 1.36(3H, t, J=6.9Hz), 4.10(2H, q, J=6.9Hz),6.80-6.86(1H, m), 7.22-7.29(1H, m), 7.30-7.41(3H, m), 7.45-7.55(2H, m),7.73-7.80(2H, m), 7.91-7.98(1H, m), 8.38-8.41(1H, m), 8.53-8.59(1H, m),12.02 91H, brs). 216 331.00 1H NMR (DMSO) 3.70-3.80(6H, m),6.81-6.90(1H, m), 7.02-7.15(2H, m), 7.32-7.40(1H, m), 7.42-7.51(2H, m),7.66-7.79(3H, m), 8.11-8.16(1H, m), 8.50-8.56(1H, m), 11.95(1H, brs).217 436.70 (400MHz, DMSO-d6) 12.31(1H, s), 8.32(1H, d), 7.94(1H, d),7.52(2H, d), 7.33(3H, m), 7.10(2H, d), 6.98(2H, d), 3.75(4H, dd) and3.15(4H, dd). 218 349.00 1H NMR (DMSO) 3.30(3H, s), 7.34-7.45(1H, m),7.49-7.83(6H, m), 8.16(1H, s), 8.18-8.28(2H, m), 8.45-8.49 91H, m),8.58-8.62(1H, m), 12.21(1H, brs). 219 342.00 1H NMR (DMSO) 3.00(6H, s),7.35-7.42(1H, m), 7.45-7.68(4H, m), 7.75-7.90(4H, m), 8.03(1H, s),8.45-8.50(1H, m), 8.56-8.60(1H, m), 12.11(1H, brs). 220 370.00 1H NMR(DMSO) 0.91(3H, t, J=7.4Hz), 1.30-1.42(2H, m), 1.49-1.59(2H, m),3.25-3.34(2H, m), 7.35-7.42(1H, m), 7.46-7.58(3H, m), 7.68-7.81(3H, m),7.92-8.03(2H, m), 8.19-8.22(1H, m), 8.44-8.49(1H, m), 8.50-8.61(2H, m),12.10(1H, brs). 221 367.00 1H NMR (DMSO) 3.36(3H, s), 7.28-7.39(2H, m),7.50-7.88(5H, m), 8.10-8.26(3H, m), 8.43-8.46(1H, m), 8.57-8.59(1H, m),12.25(1H, brs). 222 349.00 1H NMR (DMSO) 3.79(3H, s), 3.86(3H, s),7.00-7.05(1H, m), 7.26-7.37(4H, m), 7.78-7.89(2H, m), 8.35-8.40(1H, m),8.50-8.56(1H, m), 11.93(1H, brs). 223 307.00 1H NMR (DMSO) 7.22-7.37(4H,m), 7.78-7.88(4H, m), 7.92(1H, brs), 8.36-8.41 91H, m), 8.51-8.58(1H,m), 12.02(1H, brs). 224 319.00 1H NMR (DMSO) 3.80(3H, s), 6.99-7.06(2H,m), 7.26-7.36(2H, m), 7.68-7.84(5H, m), 8.33-8.39(1H, m), 8.50-8.57(1H,m), 11.91(1H, brs). 225 452.00 1H NMR (DMSO) 3.30-3.80(8H, m),7.25-7.32(1H, m), 7.50-7.63(2H, m), 7.80(1H, s), 7.88-7.99(2H, m),8.05(1H, s), 8.49-8.54(1H, m), 8.60-8.68(1H, m), 12.20(1H, brs). 226410.00 1H NMR (DMSO) 1.16(3H, t), 3.20-3.42(2H, m), 7.50-7.76(3H, m),7.88-7.95(2H, m), 7.98-8.06(2H, m), 8.20(1H, s), 8.51-8.66(3H, m),12.18(1H, brs). 227 332.00 1H NMR (DMSO) 7.28-7.39(3H, m), 7.79-8.03(7H,m), 8.09(1H, brs), 8.48-8.51(1H, m), 8.53-8.59(1H, m), 12.14(1H, brs).228 332.00 1H NMR (DMSO) 7.30-7.48(3H, m), 7.42(1H, brs), 7.50-7.58(1H,m), 7.70-7.86(3H, m), 7.92-8.11(3H, m), 8.20(1H, brs), 8.41-8.49(1H, m),8.54-8.59(1H, m), 12.09(1H, brs). 229 299.00 1H NMR (DMSO) 7.38-7.4391H, m), 7.48-7.55(2H, m), 7.78-7.83(2H, m), 7.97 92H, d, J=8.2Hz),8.09(2H, d, J=8.2Hz), 8.21(1H, s), 8.54-8.62 92H, m), 10.00 91H, s),12.30(1H, brs). 230 342.00 1H NMR (DMSO) 1.90 93H, s), 4.20-430 92H, m),7.27-7.40(3H, m), 7.45-7.51 92H, m), 7.70-7.80(4H, m), 7.85-7.91(1H, m),8.30-8.41(2H, m), 8.51-8.60(1H, m), 12.00(1H, brs). 231 313.00 1H NMR(DMSO) 2.60(3H, s), 7.36-7.42(1H, m), 7.47-7.55(2H, m), 7.76-7.83(2H,m), 7.95-8.08(4H, m), 8.15(1H, s), 8.50-8.56(1H, m), 8.58-8.63 91H, m),12.24(1H, brs). 232 286.00 1H NMR (DMSO) 5.08(2H, brs), 6.63-6.70(2H,m), 7.30-7.52 95H, m), 7.60-7.66(1H, m), 7.70-7.80(2H, m), 8.30-8.35(1H,m), 8.50-8.55(1H, m), 11.75(1H, brs). 233 1H NMR (DMSO) 2.40-2.48(3H,m), 7.36-7.55(4H, m), 7.78-7.85(4H, m), 8.02-8.09(2H, m), 8.15(1H, s),8.52-8.56(1H, m), 8.59-8.62(1H, m), 12.25(1H, brs). 234 364.00 1H NMR(DMSO) 3.00(3H, s), 7.25-7.54(5H, m), 7.70-7.90(5H, 8.93 m),8.40-8.48(1H, m), 8.52-8.60(1H, m), 9.73(1H, brs), 12.00(1H, brs). 235304.00 1H NMR (DMSO) 7.15(1H, s), 7.35(1H, brs), 7.78(1H, s), 7.687.85-8.08(7H, m), 8.31(1H, s), 8.49 91H, brs), 8.61(1H, brs), 12.08(1H,brs). 236 320.00 1H NMR (DMSO) 7.30(1H, s), 7.60-7.76(2H, m),7.82-8.10(7H, 8.14 m), 8.55(1H, brs), 8.70(1H, s), 12.10(1H, brs). 237370.00 (400MHz, MeOH-d4): 4.70-4.85(2H, brs), 6.35-6.45(1H, 4.87 s),7.30-7.50(5H, m), 8.05-8.15(1H, d), 8.20-8.25(1H, s), 8.60-8.70(1H, brs)238 388.00 1H NMR (DMSO-d6): 3.33(1H, s), 4.75-4.80(2H, m), 4.877.35-7.45(4H, m), 8.15(1H, s), 8.20-8.25(2H, m), 8.28-8.35 1H, m),8.50(1H, s) 239 344.00 1H NMR (DMSO) 3.85(3H, s), 6.91-7.00(1H, m),7.26-7.49(4H, 8.38 m), 7.85-8.10(6H, m), 8.50(1H, brs), 8.60(1H, brs),12.15(1H, brs). 240 308.24 1H NMR (DMSO-d6): 7.22(1H, m), 7.47(2H, m),7.85(1H, 4.93 s), 8.21(1H, s), 8.64(1H, s), 11.19(1H, br s) 241 299.381H NMR (CDCl3): 2.04(4H, s), 3.53(4H, s), 6.22(1H, d), 5.15 6.86(1H, d),7.44(1H, t), 7.81(1H, s), 8.17(1H, s), 8.87(1H, s) 242 369.00 1H NMR(DMSO-d6): 4.60-4.70(2H, m), 6.35-6.40(1H, 4.99 d), 7.05-7.10(1H, d),7.20-7.25(1H, t), 7.35-7.45(4H, m), 8.15-8.20(2H, m), 8.55-8.60(1H, s),12.5(1H, s) 243 321.00 1H NMR (DMSO-d6): 6.70-6.75(1H, d), 6.90-6.95(1H,t), 4.84 7.30-7.35(3H, qd), 7.50-7.65(3H, m), 8.25-8.30(2H, m), 8.80(1H,s), 9.05(1H, s), 12.5(1H, s) 244 401.49 1H NMR (DMSO-d6): 4.63(2H, d),5.20(1H, br s), 6.45(1H, 5.20 d), 7.08(1H, d), 7.27(1H, t), 7.37(2H, s),7.43(1H, t), 7.64(1H, s), 8.16(2H, d), 8.39(1H, s), 12.48(1H, br s) 245513.00 (d6-DMSO, 400MHz) 3.16(3H, s), 5.30(2H, s), 7.52(1H, 4.89 d),7.60(2H, d), 7.70(1H, d), 7.81(1H, t), 7.91(2H, d), 8.17(1H, d),8.28(1H, d), 8.36(1H, s), 12.31(1H, s) 246 245.00 (d6-DMSO, 400MHz)5.98(2H, brs), 6.25(1H, d), 3.80 7.01(1H, d), 7.37(1H, t), 8.18(1H, s),8.24(1H, d), 8.96(1H, d), 12.12(1H, s) 247 413.00 (d6-DMSO, 400MHz)3.15(3H, s), 4.71(2H, s), 6.38(1H, 4.00 d), 7.06(1H, d), 7.42(1H, t),7.65(2H, d), 7.88(2H, d), 8.18(2H, s), 8.53(1H, s), 12.12(1H, s) 248372.00 1H NMR (DMSO-d6): 7.05-7.10(1H, t), 7.35-7.40(1H, 5.22 m),7.60-7.65(1H, t), 7.70-7.80(3H, m), 7.82-7.88(1H, d), 7.95(1H, s),8.25(1H, s), 8.40(1H, s), 12.5(1H, s) 249 349.00 (d6-DMSO, 400MHz)7.56-7.60(2H, m), 7.63(1H, d), 4.59 7.69(1H, d), 7.82(1H, t), 7.97(1H,s), 8.00(2H, d), 8.27(1H, s), 8.42(1H, s), 9.28(1H, s), 10.81(1H, s),12.29(1H, s) 250 345.00 (d6-DMSO, 400MHz) 1.53(9H, s), 7.56(2H, dd),4.90 7.69(1H, t), 8.25(1H, d), 8.36(1H, s), 9.30(1H, s), 10.06(1H, s),12.22(1H, s) 251 405.00 NMR (DMSO) 4.6(2H, d, CH2), 6.4(H, d, ar),7.05(H, d, 5.15 ar), 7.3(H, m, ar), 7.4(H, d, ar), 7.45(H, t, ar),7.6(H, d, ar), 7.65(H, s, ar), 8.15(2H, s, ar), 8.5(H, s, NH) and12.15(H, s, NH). 252 349.00 1H NMR (DMSO-d6): 1.50-1.55(3H, d),5.05-5.15(2H, 4.93 m), 6.30-3.35(1H, d), 6.95-7.05(1H, d), 7.10-7.15(1H,d), 7.15-7.20(1H, t), 7.25-7.40(3H, m), 7.45-7.50(2H, d), 8.15(1H, s),8.20(1H, s), 8.75(1H, s), 12.5(1H, s) 253 315.70 CDCl3 3.23(6H, m),6.45(1H, d), 7.03(1H, d), 7.43(1H, 10.37 m), 7.5-7.57(3H, m),7.70-7.73(2H, m), 7.88(1H, s), 8.65(1H, s), 9.10(1H, s), 9.25(1H, s).254 349.00 NMR (DMSO) 2.2(3H, s, CH3), 4.5(2H, s, CH2), 6.3(H, 5.03 s,ar), 6.8-7.4(7H, m, ar), 8.1-8.3(2H, m, ar) and 8.7(H, s, NH). 255407.00 1H NMR (DMSO) 3.01(3H, s), 7.28-7.39(3H, m), 7.70-8.10(8H, m),8.45(1H, brs), 8.55(1H, brs), 9.80(1H, brs), 12.14(1H, brs). 256 407.001H NMR (DMSO) 2.45(3H, brs), 7.31(1H, brs), 7.51(1H, brs),7.80-8.15(10H, m), 8.60(1H, brs), 8.67(1H, brs), 12.21(1H, brs). 257414.53 1H NMR (DMSO-d6): 1.44(9H, s), 3.41(4H, s), 3.57(4H, 2.50 d),6.69(1H, d), 7.22(1H, d), 7.57(1H, t), 8.27(2H, s), 8.67(1H, s),12.25(1H, s 258 365.40 1H NMR (DMSO-d6): 3.70(3H, s), 6.35(1H, d),6.88(2H, 4.78 d), 7.03(1H, d), 7.11(1H, t), 7.34(2H, d), 7.37(1H, t),8.18(1H, s), 8.21(1H, d), 8.76(1H, s), 12.13(1H, s) 259 329.70 CDCl31.05(3H, t), 1.7-1.8(2H, m), 3.4-3.5(2H, m), 4.99 4.6(1H, s), 6.32(1H,d), 7.03(1H, d), 7.45(1H, m), 7.5-7.6(3H, m), 7.75(2H, d), 7.78(1H, s),8.65(1H, s), 8.97(1H, s), 9.12(1H, s) 260 349.00 (400MHz, MeOH-d4):1.55-1.60(3H, d), 5.05-5.15(1H, 4.93 m), 6.30-6.35(1H, d), 6.95-7.05(1H,d), 7.10-7.15(1H, m), 7.15-7.20(1H, t), 7.25-7.40(3H, m), 7.45-7.50(2H,d), 7.95(1H, s) 8.15(1H, s), 8.75(1H, s) 261 445.00 NMR (DMSO) 4.7(2H,d, CH2), 6.35(H, d, ar), 7.15(H, d, 5.30 ar), 7.2(H, t, ar),7.3-7.55(7H, m, ar), 7.6(s, H, ar), 8.2(H, s, ar), 8.5(H, s, NH) and8.9(H, s, NH). 262 391.00 NMR (DMSO) 2.2(3H, s, Me), 4.6(2H, d, CH2),6.3(H, d, 5.14 ar), 7.05-7.1(4H, m, ar), 7.25(2H,, d, ar), 7.3-7.45(4H,m, ar), 7.6(2H, d, ar), 8.15(H, s, ar), 8.5(H, s, NH) and 9.05(H, s,NH). 263 355.00 1H NMR (DMSO-d6): 6.70-6.80(1H, d), 7.10-7.20(1H, t),4.92 7.30-7.40(2H, m), 7.50-7.60(2H, m), 7.80-7.90(1H, d), 8.15(1H, s),8.25(1H, s), 8.50(2H, s), 12.2(1H, s) 264 349.00 1H NMR (DMSO-d6):2.95-3.00(2H, t), 3.55-3.60(2H, 4.67 m), 6.30-6.35(1H, d), 6.65-6.70(1H,t), 7.05-7.10(1H, d), 7.15-7.20(1H, t), 7.30(4H, m), 7.32-7.40(1H, t),8.17(1H, s), 8.20(1H, s), 8.85(1H, s), 12.2(1H, s) 265 363.00 NMR (DMSO)6.7(H, d, ar), 6.9(H, t, ar), 7.35-7.4(2H, m, 4.64 ar), 7.4-7.5(4H, m,ar), 7.5-7.75(5H, m, ar), 8.25(H, s, ar), 8.6(H, s, ar), 8.9(H, s, ar),9.3(H, s, NH) and 12.1(1H, s, NH). 266 397.00 NMR (DMSO) 6.8(H, d, ar),7.0(H, m, ar), 7.2(H, m, ar), 5.20 7.2-7.6(7H, m, ar), 7.65(H, m, ar),8.0(H, m, ar), 8.2(H, s, ar), 8.4(H, m, NH), 8.5(H, s, ar), 8.7(H, s,ar) and 12.1(H, brs, NH). 267 314.43, 314.00 1H NMR (DMSO-d6): 3.11(4H,s), 3.88(4H, d), 6.78(1H, 3.42, 2.75 d), 7.30(1H, d), 7.65(1H, t),8.30(2H, d), 8.63(1H, s), 8.77(2H, br s), 12.30(1H, s), DMSO D62.82-2.93(4H, m), 3.48-3.55(4H, m), 6.65(1H, d), 7.15(1H, d), 7.55(1H,t), 8.25-8.30(2H, m), 8.69(1H, s) 268 287.60 CDCl3 4.48(2H, s), 6.45(1H,d), 7.12(1H, d), 7.42(1H, t), 2.79 7.5-7.6(3H, m), 7.75(2H, t), 7.88(1H,s), 8.7(1H, s), 8.88(1H, s), 9.52(1H, s) 269 377.60 CDCl3 4.7(2H, d),5.0(1H, s), 6.35(1H, d), 7.08(1H, d), 5.00 7.3-7.4(9H, t), 7.5-7.6(3H,m), 7.68(2H, d), 7.88(1H, s), 8.65(1H, s), 8.95(1H, s), 9.43(1H, s) 270289.00 1H NMR (DMSO-d6): 3.45-3.50(2H, m), 3.60-3.65(2H, 3.79 m),4.70-4.77(1H, t), 6.25-6.30(1H, d), 6.50-6.55(1H, t), 7.00-7.05(1H, d),7.30-7.40(1H, t), 8.20(1H, s), 8.25(1H, s), 8.85(1H, s), 12.2(1H, s) 271330.00 1H NMR (DMSO-d6): 2.00-2.10(2H, m), 2.80-2.85(6H, 3.34 s),3.20-3.30(2H, m), 3.40-3.50(2H, m), 6.25-6.30(1H, m), 6.60-6.80(1H, m),7.00-7.05(1H, d), 7.30-7.40(1H, t), 8.20-8.30(2H, m), 8.85(1H, s),12.2(1H, s) 272 225.00 (d6-DMSO) 2.90(3H, d), 6.24(1H, d), 6.42-6.44(1H,m), 3.32 7.00(1H, d), 7.14(1H, dd), 7.37(1H, t), 8.08(1H, s), 8.23(1H,d), 8.85(1H, d), 11.87(1H, s) 273 355.00 1H NMR (DMSO-d6): 6.60-6.65(1H,m), 6.70-6.80(1H, d), 7.00-7.10(1H, m), 7.15-7.30(1H, m), 7.20-7.30(1H,m), 7.55-7.65(2H, m), 7.90(1H, s), 8.15(1H, s), 8.30(1H, s), 8.60(1H,s), 8.90-8.95(1H, m), 12.2(1H, s) 274 349.48 1H NMR (DMSO-d6): 3.14(3H,s), 4.92(4H, s), 6.42(1H, 5.25 d), 7.09(1H, d), 7.23(1H, t), 7.31(4H,m), 7.48(1H, t), 8.11(1H, s), 8.21(1H, s), 8.55(1H, s), 12.20(1H, br s)275 328.46 1H NMR (DMSO-d6): 2.24(3H, s), 3.31(4H, s), 3.56(4H, 4.37 s),6.67(1H, d), 7.19(1H, d), 7.54(1H, t), 8.27(2H, s), 8.69(1H, s),12.23(1H, s) 276 354.64 1H NMR (DMSO-d6): 2.07(3H, s), 3.57(8H, m),6.70(1H, 4.25 d), 7.23(1H, d), 7.58(1H, t), 8.28(2H, s), 8.68(1H, s),12.25(1H, s) 277 331.70 DMSO 3.55(1H, m), 3.65(1H, m), 4.82(1H, m),6.35(1H, 4.24 d), 6.52(1H, m), 7.05(1H, d), 7.4(1H, t), 7.55(1H, t),7.75(1H, d), 8.15(1H, s), 8.58(1H, s), 9.08(1H, s) 278 301.70 DMSO2.92(3H, s), 6.30(1H, d), 6.51(1H, m), 7.08(1H, d), 4.62 7.35-7.42(2H,m), 7.5-7.6(2H, m), 7.72(2H, d), 8.13(1H, s), 8.65(1H, s), 9.18(1H, s)279 315.00 NMR (DMSO) 1.1(6H, d, iPr), 2.85(H, m, CH), 3.3(H, 4.47 brs,NH), 7.55(H, d, ar), 7.65(H, t, ar), 7.85(H, t, ar), 8.2(H, s, ar),8.3(H, s, ar), 9.1(H, s, ar) and 10.3(H, s, NH). 280 363.00 NMR (DMSO)3.85(2H, s, CH2), 7.15(5H, m, ar), 7.6(H, 4.72 d, ar), 7.7(H, t, ar),7.9(h, d, ar), 8.3(H, s, ar), 84(H, s, ar), 9.1(H, s, ar), 10.6(H, s,NH) and 12.3(H, brs, NH). 281 383.00 (DMSO) 7.45-7.7(3H, m, ar),7.7-7.8(2H, m, ar), 7.8(H, t, 4.68 ar), 8.0(H, m, ar), 8.25(H, s, ar),8.4(H, s, ar), 9.2(H, s, ar), 11.1(H, s, NH), and12.3(H, s, NH). 282383.00 DMSO) 6.6(H, m, ar), 7.7(2H, d ar), 7.85(H, t, ar), 8.0(H, 4.95m, ar), 8.1(H, s, ar), 8.25(H, s, ar), 8.45(H, s, ar), 9.3(H, s, ar),10.8(0.5H, s, NH) and 12.3(0.5H, s, NH). 283 287.00 (DMSO) 2.2(3H, s,Me), 7.55(H, m, ar), 7.7(H, m, ar), 4.05 7.85(H, m, ar), 8.2(H, m, ar),8.4(H, m, ar), 10.4(H, s, NH) and 12.3(H, s, NH) 284 335.00 1H NMR(DMS-d6): 3.50-3.55(3H, m), 6.40-6.45(1H, 5.27 m), 7.25-7.30(2H, m),7.32-7.37(2H, m), 7.45-7.55(3H, m), 8.15(1H, s), 8.30(1H, s), 8.45(1H,s), 12.2(1H, s) 285 386.46 1H NMR (CDCl3): 1.69(3H, d, J=6.9Hz),5.29(1H, m), 4.97 5.42(1H, 6.8Hz), 7.07(2H, m), 7.44(2H, m), 8.04(1H,m), 8.09(1H, m), 8.27(1H, m), 8.65(1H, m), 8.87(1H, br s) 286 368.46 1HNMR (CDCl3): 1.69(3H, d, J=6.8), 5.33(1H, m), 5.45(1H, 4.90 m), 7.38(2H,m), 7.47(2H, m), 8.04(1H, d), 8.08(1H, d), 8.27(1H, d), 8.70(2H, m) 287369.80 DMSO 1.1-1.3(6H, m), 1.6-1.7(2H, m), 2.0-2.08(2H, m), 5.274.0(1H, m), 6.26(1H, d), 6.35(1H, d), 7.0(1H, d), 7.3-7.4(2H, m),7.52(2H, t), 7.7(2H, d), 8.15(1H, s), 8.55(1H, s), 9.1(1H, s) 288 355.00(DMSO) 1.1-1.5(5H, m, cyhex), 1.6-1.9(5H, m, cyhex), 4.95 2.65(1H, m,cyhex), 7.6(H, d, ar), 7.75(H, t, ar), 7.95(H, d, ar), 8.3(H, s, ar),8.4(H, s, ar), 9.15(H, s, ar), 10.35(H, s, NH) and 12.2(H, s, NH). 289313.45 1H NMR (DMSO-d6): 1.55(6H, m), 2.01(2H, s), 4.20(1H, 5.09 m),6.27(1H, d), 6.54(1H, d), 7.01(1H, d), 7.34(1H, t), 8.23(1H, s),8.30(1H, s), 8.96(1H, s), 12.13(1H, s) 290 327.45 1H NMR (DMSO-d6):1.27(3H, m), 1.45(2H, m), 1.69(1H, 5.25 d), 1.81(2H, d), 2.09(2H, d),3.81(1H, m), 6.24(1H, d), 6.39(1H, d), 6.97(1H, d), 7.31(1H, t),8.20(2H, s), 8.88(1H, s), 12.20(1H, br s) 291 341.49 1H NMR (DMSO-d6):1.51(6H, m), 1.67(4H, m), 2.01(2H, 5.37 2), 4.02(1H, s), 6.26(1H, d),6.44(1H, d), 6.98(1H, d), 7.33(1H, t), 8.19(1H, s), 8.24(1H, s),8.93(1H, s), 12.13(1H, br s) 292 273.38 1H NMR (DMSO-d6): 2.94(3H, s),3.53(3H, s), 6.56(1H, 4.59 s), 7.05(1H, s), 7.58(1H, s), 8.31(1H, s),8.36(1H, s), 8.78(1H, s) 293 341.55 1H NMR (CDCl3): 2.04(4H, m),3.61(4H, m), 6.24(1H, d, 5.32 J=8.3), 6.98(1H, d, J=7.4), 7.39(1H, m),7.48-7.52(3H, m), 7.70(2H, m), 7.88(1H, m), 8.61(1H, s), 9.16(1H, s),9.33(1H, br s) 294 350.00 DMSO) 7.7-7.8(2H, m, ar), 7.9(H, t, ar),8.05(H, d, ar), 4.85 8.15(H, t, ar), 8.25(H, d, ar), 8.3(H, s, ar),8.45(H, s, ar), 8.8(H, d, ar), 9.0(H, s, ar), 10.6(H, s, NH) and 12.4(H,s, NH). 295 383.00 (400MHz, MeOH-d4): 7.85-7.95(2H, d), 8.05-8.10(2H,3.98 d), 8.25-8.30(2H, s), 8.35-8.37(1H, s), 8.70(1H, s) 296 350.00(DMSO) 7.6-7.7(H, m, ar), 7.75(H, m, ar), 7.85(H, m, ar), 4.22 8.0(H, m,ar), 8.3(H, m, ar), 8.4(H, m, ar), 8.8(H, s, ar), 9.15(h, s, ar), 9.3(H,s, ar), 11.0(H, s, ar) and 12.35(H, s, NH) 297 395.55 1H NMR (DMSO-d6):3.69(6H, d), 4.41(2H, br s), 6.34(1H, 4.64 s), 6.88(2H, m), 6.94(2H, s),7.02(1H, m), 7.36(1H, t), 8.19(2H, m), 8.76(1H, s), 12.13(1H, s) 298257.59 1H NMR (DMSO-d6): 2.89(3H, s), 6.26(1H, d), 6.54(1H, 4.40 d),7.03(1H, d), 7.38(1H, t), 8.21(1H, s), 8.24(1H, s), 8.94(1H, s),12.14(1H, s) 299 354.00 (400MHz, MeOH-d4): 2.35-2.40(3H, s),7.30-7.45(4H, 4.87 m), 8.05-8.15(3H, m), 8.20-8.25(1H, s) 300 368.00(400MHz, DMSO-d6): 2.20(6H, s), 7.25(3H, m), 7.70-7.80(1H, 4.93 s),8.05(1H, m), 8.15(1H, m), 8.30(1H, m), 9.10(1H, s), 12.2(1H, s) 301406.00 (400MHz, DMSO-d6): 7.80-7.85(1H, m), 7.90-7.95(2H, 4.53 d),8.05-8.10(2H, d), 8.15-8.35(3H, m), 8.50(1H, s), 8.60(1H, s),9.50-9.55(1H, s), 9.85-9.90(1H, s), 12.2(1H, s) 302 (400MHz, MeOH-d4):2.10-2.0(1H, m), 2.70-2.80(1H, m), 2.95-3.05(1H, m), 3.10-3.20(1H, m),5.90-6.00(1H, t), 7.20-7.40(4H, m), 8.05-8.10(1H, s), 8.15-8.20(2H, d),8.85(1H, s) 303 342.60 (DMSO) 2.9-3.1(4H, m), 7.0-7.5(6H, m),7.7-7.8(2H, m), 4.30 7.8-8.2(6H, m), 11.9(0.7H, s) 304 346.50 (DMSO)7.1-7.2(3H, m), 7.2-7.4(3H, m), 7.8-7.9(2H, m), 4.34 7.9-8.1(3H, m),8.1-8.2(1H, s), 8.4(1H, s), 8.5(1H, s), 12.3-12.4(0.7H, s) 305 398.00(400MHz, CDCl3): 1.65-1.70(3H, d), 5.25-5.30(1H, m), 4.87 5.40-5.45(1H,m), 6.80-6.85(1H, d), 7.0(1H, s), 7.05-7.10(1H, d), 7.30-7.35(1H, t),8.05-8.10(2H, m), 8.30(1H, s), 8.70(1H, s), 9.20-9.50(1H, brs) 306384.00 (400MHz, MeOH-d4): 1.65-1.70(3H, d), 5.40-5.50(1H, 4.45 m),6.65-6.80(1H, d), 6.95(1H, s), 7.00-7.05(1H, d), 7.15-7.20(1H, t),8.00-8.10(2H, m), 8.20(1H, s), 8.70(1H, s) 307 410.80 CDC13 1.7(3H, d),3.97(3H, s), 5.42(1H, br s), 4.64 5.57(1H, m), 7.03(2H, t), 7.5-7.6(2H,m), 8.12(1H, s), 8.2(1H, s), 9.1(1H, s), 9.52(1H, s), 10.15(1H, br s)308 405.00 (d6-DMSO, 400MHz) 4.73(2H, s), 7.38(2H, d), 7.54(2H, 5.50 d),8.30(1H, d), 8.50(1H, s), 8.62(2H, d) 309 409.80 DMSO 1.62(3H, d),2.88(3H, m), 5.58(1H, d), 7.1(2H, m), 3.95 7.62(2H, m), 8.1-8.25(3H, m),8.55(1H, m), 8.72(1H, s), 9.15(1H, s), 12.3(1H, s) 310 413.51 1H NMR(DMSO-d6): 1.58(3H, d), 5.50(1H, t), 7.67(2H, 4.82 d), 7.79(2H, d),8.16(3H, m), 8.21(2H, d), 8.37(1H, s) 311 402.48 1H NMR (DMSO-d6):1.71(3H, d), 5.43(1H, m), 7.28(1H, 4.89 s), 7.54(2H, d), 7.61(2H, d),7.66(1H, s), 7.94(1H, s), 8.26(1H, s), 8.47(1H, s), 12.49(1H, s) 312388.42 1H NMR (DMSO-d6): 4.74(2H, d), 7.28(1H, t), 7.38(2H, 4.95 m),7.48(1H, s), 8.19(1H, s), 8.23(2H, m), 8.33(1H, t), 8.52(1H, s),12.33(1H, s) 313 383.50 1H NMR (DMSO-d6): 1.66(3H, d), 5.45(1H, q), 6.854.64(2H, d), 7.31(1H, s), 8.20(1H, d), 8.23(1H, s), 8.54(2H, d) 314389.00 (d6-DMSO, 400MHz) 5.69(2H, s), 7.49(2H, d), 7.59(2H, 5.32 d),8.32(1H, s), 8.42(1H, s), 8.65-8.67(2H, m), 12.56(1H, s) 315 306.46 1HNMR (DMSO-d6): 4.48(1H, m), 8.23(1H, s), 8.35(2H, 4.80 m), 8.68(1H, s),12.59(1H, s) 316 355.46 1H NMR (DMSO-d6): 4.87(2H, d), 7.36(1H, m),7.51(1H, 4.10 d), 7.87(1H, m), 8.12(1H, s), 8.24(1H, s), 8.29(1H, d),8.43(1H, s), 8.62(2H, d), 12.39(1H, s) 317 355.46 1H NMR (DMSO-d6):4.86(2H, d), 7.73(1H, m), 8.26(2H, 4.10 s), 8.30(1H, d), 8.44(1H, s),8.54(1H, s), 8.65(1H, d), 8.86(1H, s) 12.43(1H, s) 318 355.46 1H NMR(DMSO-d6): 4.93(2H, d), 7.90(2H, d), 8.16(1H, 4.00 s), 8.23(2H, d),8.31(1H, s), 8.55(1H, s), 8.78(2H, d), 12.37(1H, s) 319 231.38 1H NMR(DMSO-d6): 7.27(1H, t), 8.32(1H, s), 8.41(1H, 4.20 s), 8.80(3H, m) 320455.00 1H NMR (DMSO-d6): 1.55-1.60(3H, d), 2.15-2.20(6H, 4.49 s),2.55-2.60(2H, m), 3.95-4.00(2H, m), 5.35-5.40(1H, m), 6.60-6.40(1H, m),7.00-7.10(2H, m), 7.15-7.20(1H, t), 8.05-8.10(1H, m), 8.15-8.20(2H, m),8.25(1H, s), 8.60(1H, s), 12.2(1H, s) 321 453.00 1H NMR (DMSO-d6):1.60-1.70(3H, d), 2.20-2.30(2H, 4.25 m), 3.4-3.5(4H, m), 5.15-5.20(1H,m), 5.55-5.62(1H, m), 6.85-6.90(1H, d), 7.05-7.10(1H, s), 7.18-7.23(1H,d), 7.35-7.40(1H, t), 8.30-8.35(3H, m), 8.50(1H, s) 322 382.00 NMR(DMSO) 1.65(3H, d, CH3), 2.15(3H, s, CH3), 5.55(H, 4.99 m, alpha),7.1(H, d, ar), 7.1-7.2(2H, m, ar), 7.6(2H, m, ar), 8.05(1H, s, ar),8.2(1H, s, ar), 8.3(1H, s, ar), 8.63(1H, s, ar) and 12.3(1H, s, ar) 323412.00 NMR (DMSO) 1.5(3H, d, CH3), 5.4(H, m alpha), 7.0(H, 4.10 s, ar),7.1-7.25(2H,, m, ar), 7.5-7.6(2H, m, ar), 8.3(H, s, ar), 8.4(2H, brs,ar), 8.65(H, s, ar) and 12.4(H, s, ar). 324 382.00 NMR (DMSO) 1.5(3H, s,CH3), 2.25(3H, s, CH3), 5.3(H, 4.92 m, alpha), 6.2(H, m, ar), 7.3(2H, m,ar), 7.5(2H, m, ar) 7.75(H, m, ar), 8.2(H, m, ar), 8.3(H, m, ar),8.65(H, m, ar) and 12.3(H, m, ar) 325 361.44 1H NMR (DMSO-d6): 1.53(3H,m), 1.81(2H, m), 1.98(1H, 3.70 m), 2.90(1H, m), 3.31(1H, m), 3.43(1H,m), 3.58(2H, m), 7.85(1H, s), 8.30(2H, d), 8.36(1H, s), 8.68(1H, d),8.84(1H, s), 12.52(1H, s) 326 361.44 1H NMR (DMSO-d6): 1.34(1H, m),1.60(1H, m), 1.92(2H, 3.59 m), 2.20(1H, m), 2.78(2H, m), 3.24(3H, m),3.54(1H, m), 7.99(1H, s), 8.23(1H, m), 8.30(2H, d), 8.60(1H, d),8.70(1H, s), 12.45(1H, s) 327 361.44, 361.00 1H NMR (DMSO-d6): 1.41(2H,m), 1.92(2H, m), 2.08(1H, 3.57, m), 2.83(2H, m), 3.29(2H, m), 3.44(2H,m), 7.97(1H, 3.55 s), 8.20(1H, s), 8.25(1H, s), 8.30(1H, s), 8.48(1H,d), 8.71(1H, s), 12.43(1H, s), 1H NMR (DMSO-d6): 1.41(2H, m), 1.92(2H,m), 2.08(1H, m), 2.83(2H, m), 3.29(2H, m), 3.44(2H, m), 8.20(1H, s),8.25(1H, s), 8.30(1H, s), 8.48(1H, d), 8.71(1H, s), 12.43(1H, s) 328347.40 1H NMR (DMSO-d6): 1.94(1H, m), 1.96(2H, m), 2.14(1H, 3.67 m),3.20(2H, m), 3.71(2H, m), 3.83(1H, m), 7.89(1H, s), 8.30(4H, m),8.69(1H, s), 8.91(1H, s), 12.58(1H, s) 329 347.40 1H NMR (DMSO-d6):1.77(1H, m), 2.12(1H, m), 2.77(1H, 3.54 m), 3.00(1H, m), 3.17(1H, m),3.34(2H, m), 3.60(2H, m), 7.98(1H, s), 8.23(1H, d), 8.31(2H, m),8.71(3H, m), 12.53(1H, s) 330 394.45 1H NMR (DMSO-d6): 2.04(4H, m),2.84(2H, m), 3.33(1H, 5.28 s), 5.61(1H, m), 7.18(3H, m), 7.27(1H, d),8.00(1H, d), 8.21(1H, t), 8.23(1H, s), 8.26(1H, s), 8.68(1H, s),12.34(1H, s) 331 483.00 (d6-DMSO, 400MHz) 1.44(9H, s), 1.54(3H, d),5.34-5.37(1H, 4.95 m), 7.11(1H, brs), 7.19(2H, d), 7.63(1H, s),8.10-8.12(2H, m), 8.18(1H, d), 8.23(1H, d), 8.54(1H, d), 9.27(1H, brs),12.29(1H, brs) 332 264.00 NMR (DMSO) 7.3(2H, brs, NH2), 8.1(1H, s, ar),8.2(1H, 3.87 s, ar), 8.3(1H, s, ar), 8.95(1H, s, ar) and 12.35(1H, s,NH). 333 383.00 (d6-DMSO, 400MHz) 1.55(3H, d), 5.36-5.40(1H, m), 4.426.76(1H, brs), 6.98(1H, brs), 7.21(2H, brs), 8.16(1H, d), 8.23(1H, d),8.26(2H, d), 8.58(1H, s), 12.36(1H, s) 334 382.80 DMSO 1.58(3H, d),4.65(2H, d), 5.28(1H, t), 5.5-5.6(1H, 3.90 m), 7.15(2H, m), 7.6(2H, m),8.05(1H, m), 8.2(1H, s), 8.26(1H, m), 8.68(1H, s), 11.95(1H, s) 335456.00 1H NMR (MeOD-d4): 1.60-1.70(3H, d), 3.60(3H, s), 4.65(2H, 4.70s), 5.40-5.45(1H, m), 6.70-6.75(1H, d), 7.03(1H, s), 7.12-7.18(1H, d),7.25-7.30(1H, t), 8.00-8.07(2H, m), 8.15(1H, s), 8.60(1H, s) 336 442.001H NMR (DMSO-d6): 1.35-1.40(3H, d), 4.00-4.05(2H, 3.82 s), 5.25-5.35(1H,m), 6.50-6.55(1H, d), 6.95-7.00(2H, m), 7.05-7.15(1H, m), 8.05-8.13(3H,m), 8.18(1H, s), 8.55(1H, s), 12.5(1H, s) 337 363.00 1H NMR (CD3OD):1.60-1.70(3H, d), 3.10-3.20(3H, s), 4.07 3.35-3.45(3H, s), 5.30-5.35(1H,m), 8.15-8.20(2H, m), 8.30-8.35(1H, s), 8.75-8.80(1H, s) 338 375.00 1HNMR (DMSO-d6): 0.30-0.40(1H, m), 0.42-0.47(1H, 3.84 m), 1.35-1.40(3H,d), 2.55-2.60(1H, m), 4.40-4.50(1H, m), 7.58-7.63(1H, d), 8.15-8.25(3H,m), 8.28(1H, s), 8.65(1H, s), 12.0(1H, s) 339 398.47 1H NMR (CDCl3):1.63(3H, m), 3.44(1H, s), 4.57(2H, 4.59 m), 5.31(1H, br s), 6.02(1H, brs), 7.06(2H, m), 7.39(2H, m), 8.19(1H, m), 8.30(1H, m), 8.76(1H, br s),8.93(1H, br s) 340 349.00, 349.00 1H NMR (DMSO-d6): 1.35-1.40(3H, d),2.55-2.60(3H, 3.59, m), 4.40-4.50(1H, m), 7.58-7.63(1H, d),8.00-8.05(1H, 2.84 m), 8.15-8.25(2H, m), 8.28(1H, s), 8.65(1H, s),12.0(1H, s), 1H NMR (DMSO-d6): 1.35-1.40(3H, d), 2.55-2.60(3H, m),4.40-4.50(1H, m), 7.58-7.63(1H, d), 8.00-8.05(1H, m), 8.15-8.25(2H, m),8.28(1H, s), 8.65(1H, s), 12.0(1H, s) 341 428.00 1H NMR (DMSO-d6):1.35-1.40(3H, d), 3.6-3.7(2H, m), 4.47 3.95-4.00(2H, m), 4.80-4.90(1H,m), 5.4-5.5(1H, m), 6.7-6.8(1H, m), 7.00-7.10(2H, m), 7.20-7.25(1H, m),8.10-8.25(3H, m), 8.65(1H, s), 12.0(1H, s) 342 (400MHz, DMSO) 1.57(3H,d), 5.50-5.57(1H, m), 7.11-7.15(2H, m), 7.57-7.60(2H, m), 8.20(1H, d),8.25(1H, d), 8.36(1H, s), 9.15(1H, d), 9.45(1H, d), 12.90(1H, brs). 343(400MHz, DMSO) 1.55(3H, d), 4.85(2H, s), 5.45-5.53(1H, m), 7.09-7.14(2H,m), 7.55-7.58(2H, m), 7.62(1H, s), 7.72(1H, d), 7.87(1H, s), 7.95(1H,d), 8.10(1H, d), 11.55(1H, s). 344 333.00 1H NMR (CD3OD): 2.40-2.50(2H,m), 2.6-2.7(2H, m), 3.54 3.50-3.60(3H, m), 3.7-3.8(1H, m), 5.2-5.3(1H,m), 8.40(1H, s), 8.50(1H, m), 8.55(1H, s), 8.75(1H, s) 345 347.00,347.40 1H NMR (DMSO-d6): 1.80-1.90(2H, m), 2.1-2.2(2H, m), 3.50,3.05-3.15(2H, m), 3.4-3.5(2H, m), 4.30-4.40(1H, m), 3.50 7.65-7.70(1H,m), 8.30-8.35(2H, m), 8.40-8.50(1H, s), 8.60-8.70(1H, s), 8.75-8.80(1H,m), 12.0(1H, s), 1H NMR (DMSO-d6): 1.84(2H, m), 2.33(2H, m), 3.14(2H,m), 3.44(2H, m), 4.36(1H, m), 7.88(1H, s), 8.25(1H, s), 8.30(2H, d),8.37(1H, m), 8.60(1H, m), 8.69(1H, s), 12.44(1H, s) 346 423.56 1.73(3H,d, J 6.8, Me), 3.06(3H, br s, Me), 3.24(3H, br 4.02 s, Me),5.53-5.47(1H, m, CH), 5.75(1H, br s, NH), 7.07-7.03(2H, m, 2 × ArH),7.46-7.43(2H, m, 2 × ArH), 8.14(1H, d, J 3.7, ArH), 8.46(1H, d, J 1.8,ArH), 8.77(2H, s, 2 × ArH). 347 347.47 1H NMR (DMSO-d6): 1.66(1H, m),1.85(1H, m), 1.98(1H, 3.68 m), 2.11(1H, m), 2.90(2H, m), 3.32(1H, m),3.47(1H, m), 4.46(1H, m), 7.57(1H, d), 8.31(3H, m), 8.66(3H, m),12.47(1H, s) 348 348.44 1H NMR (DMSO-d6): 1.67(2H, m), 1.96(2H, d),3.49(2H, 4.42 t), 3.96(2H, d), 4.30(1H, m), 7.62(1H, d), 8.18(1H, s),8.22(1H, s), 8.29(1H, s), 8.72(1H, s), 12.36(1H, s) 349 360.46 1H NMR(DMSO-d6): 1.17(5H, m), 1.70(6H, m), 2.67(2H, 5.39 d), 8.27(1H, s),8.42(2H, s), 8.72(1H, s), 12.57(1H, s) 350 396.46 (DMSO, D6); 1.55(3H,d, J 6.8, Me), 5.53(1H, t, J 6.8, 3.27 CH), 7.13-7.09(2H, m, 2 × ArH),7.63-7.60(2H, m, 2 × ArH), 8.15-8.14(1H, m, NH), 8.22-8.19(2H, m, 2 ×ArH) 8.83(1H, s, ArH), 9.30(1H, s, ArH). 351 392.00 1H NMR (DMSO-d6):1.35-1.40(9H, s), 1.50-1.55(3H, 4.87 d), 4.10-4.15(1H, m) 4.40-4.50(1H,m), 7.95-8.00(1H, d), 8.20(1H, s), 8.30(1H, m), 8.35(1H, m), 8.75(1H, s)352 347.00 (d6-DMSO, 400MHz) 1.86-1.94(1H, m), 2.28(3H, s), 4.002.33(1H, brs), 2.53-2.57(1H, m), 2.60-2.67(2H, m), 2.84-2.88(1H, m),4.62(1H, brs), 7.67(1H, d), 8.17(1H, d), 8.21(1H, s), 8.28(1H, d),12.35(1H, s) 353 255.00 DMSO D6 7.60(1H, d), 8.32(1H, s), 8.43(1H, s),8.56(1H, 4.52 s), 8.82-8.86(2H, m) 12.55(1H, s). 354 382.46 1H NMR(DMSO-d6): 0.95(3H, t), 1.85(1H, m), 1.97(1H, 4.92 m), 7.19(1H, t),7.34(2H, t), 7.53(2H, d), 8.08(1H, d), 8.16(2H, s), 8.26(1H, s),8.66(1H, s), 12.31(1H, s) 355 374.50 1H NMR (DMSO-d6): 1.15(8H, m),1.28(2H, m), 1.72(2H, 5.47 m), 1.84(2H, m), 4.23(1H, m), 7.43(1H, d),8.12(1H, s), 8.18(1H, s), 8.27(1H, s), 8.73(1H, s), 12.32(1H, s) 356346.43 1H NMR (DMSO-d6): 0.85(1H, m), 1.48(4H, m), 1.68(1H, 5.25 d),1.81(2H, m), 2.04(2H, m), 4.03(1H, m), 7.49(1H, d), 8.13(1H, s),8.19(1H, s), 8.29(1H, s), 8.73(1H, s), 12.21(1H, s) 357 432.70 CDCl30.8(3H, d), 5.45(1H, m), 5.6(1H, br s), 7.1(2H, m), 5.00 7.45(2H, m),8.15(1H, s), 8.4(1H, s), 8.5-8.6(1H, brs), 8.78(1H, s), 9.65(1H, br s)358 439.00 (DMSO) 1.27(3H, t, J 7.1), 1.56(3H, d, J 7.0), 4.17(2H, 4.39q, J 7.1), 5.64(1H, t, J 7.0), 7.10(2H, t, J 8.9), 7.60-7.56(2H, m),8.04-8.00(2H, m), 8.15(1H, d, J 3.8), 8.22(1H, d, J 2.1), 8.96(1H, brs), 9.65(1H, br s), 11.96(1H, br s). 359 425.51 1H NMR (DMSO): 1.52(3H,m), 2.85(3H, m), 5.33(1H, 4.82 m), 7.00(1H, s), 7.15(2H, m), 7.48(2H,m), 8.24(2H, m), 8.49(1H, s), 8.66(1H, s), 8.87(1H, m), 12.4(1H, br s)360 336.00 1H NMR (DMSO-d6): 1.45-1.50(3H, d), 4.50-4.60(1H, 3.20 m),8.05-8.25(5H, m), 8.60(1H, m), 12.3-12.4(1H, s), 12.50-1.270(1H, brs)361 363.00 1H NMR (CD3OD): 1.10-1.20(3H, t), 1.90-2.20(2H, m), 3.922.85(3H, s), 4.65-4.70(1H, m), 8.25-8.35(3H, m), 8.65(1H, s) 362 377.001H NMR (CD3OD): 1.10-1.20(6H, m), 2.3-2.4(1H, m), 4.27 2.80(3H, s),4.70-4.75(1H, d), 8.25-8.35(3H, m), 8.80(1H, s) 363 377.00 1H NMR(CD3OD): 1.05-1.15(6H, m), 1.50-1.60(3H, m), 4.07 3.95-4.05(1H, m),4.50-4.65(1H, m), 8.10-8.25(3H, m), 8.80(1H, s) 364 391.00 1H NMR(CD3OD): 0.70-0.80(6H, m), 1.55-1.60(3H, d), 4.22 1.70-1.80(1H, m),2.85-2.95(1H, m), 3.10-3.15(1H, m), 4.50-4.65(1H, m), 8.10-8.25(3H, m),8.80(1H, s) 365 381.00 1H NMR (CD3OD): 1.55-1.60(3H, d), 3.45-3.55(2H,m), 3.79 4.25-4.35(1H, m), 4.40-4.45(1H, m), 4.55-4.65(1H, m),8.10-8.25(3H, m), 8.80(1H, s) 366 362.00 (d6-DMSO, 400MHz) 1.23-1.33(2H,m), 1.72(2H, d), 4.50 1.99-2.04(1H, m), 3.27(2H, t), 3.41(2H, t),3.85-3.89(2H, m), 7.80(1H, t), 8.14(1H, d), 8.21(1H, s), 8.28(1H, d),8.74(1H, d), 12.35(1H, brs) 367 363.00 1H NMR (DMSO-d6): 0.95-1.05(3H,t), 1.35-1.40(3H, d), 3.92 3.00-3.10(2H, m), 4.45-4.55(1H, m),7.55-7.60(1H, d), 8.05-8.10(1H, m), 8.18-8.22(2H, m), 8.28(1H, s),8.70(1H, s), 368 456.00, 456.07 1H NMR (DMSO-d6): 1.40-1.50(3H, d),2.80(3H, s), 3.57, 2.85-3.05(2H, m), 3.15-3.25(2H, m), 4.50-4.60(1H, m),2.84 7.00-7.05(1H, m), 7.60-7.65(1H, d), 8.12-8.17(1H, m), 8.19(1H, m),8.22(1H, m), 8.28(1H, s), 8.70(1H, s),, 1H NMR (DMSO): 1.45(3H, d),2.89(2H, m), 3.15(2H, m), 3.31(3H, s), 4.55(1H, m), 7.04(1H, s),7.69(1H, d), 8.19(2H, m), 8.26(1H, s), 8.67(1H, s), 12.35(1H, s) 369417.00, 416.90 1H NMR (CD3OD): 1.55-1.60(3H, d), 3.85-4.00(2H, m), 4.09,4.70-4.80(1H, m), 8.10-8.25(3H, m), 8.80(1H, s), DMSO 2.30 d6 12.4(bs,1H); 8.8(t, 1H); 8.7(s, 1H); 8.3(s, 2H); 8.2(s, 1H); 7.9(bs, 1H); 4.7(q,1H); 4.0(m, 2H); 1.3(d, 3H) 370 412.44 1H NMR (DMSO): 1.60(3H, m),5.51(1H, br s), 7.08-7.21(2H, 4.22 m), 7.49-7.53(2H, m), 8.29(1H, m),8.39(1H, m), 8.53(1H, m), 8.79(2H, m), 12.6(1H, s) 371 436.48 1H NMR(CDCl3): 1.64(3H, m), 5.31(1H, m), 5.77(1H, 5.17 m), 7.05(2H, m),7.40(2H, m), 7.95(1H, m), 8.32(1H, br s), 8.58(1H, m), 8.94(1H, m) 372375.00 (d6-DMSO, 400MHz) 1.14-1.24(2H, m), 1.75-1.80(5H, 3.95 m),2.11(3H, s), 2.75(2H, d), 3.40(2H, t), 7.80(1H, t), 8.13(1H, d),8.20(1H, s), 8.28(1H, d), 8.73(1H, d), 12.35(1H, s) 373 348.00 (d6-DMSO,400MHz) 1.66-1.74(1H, m), 1.99-2.08(1H, 3.27 m), 2.67-2.74(1H, m),3.49-3.51(2H, m), 3.58-3.67(2H, m), 3.73(1H, t), 3.79-3.84(1H, m),7.88(1H, t), 8.16(1H, d), 8.22(1H, s), 8.29(1H, d), 8.74(1H, d),12.36(1H, brs) 374 376.70 CDCl3 1.75(3H, d), 3.23(1H, s), 5.30-5.35(1H,m), 5.5-5.56(1H, 3.54 m), 7.08-7.18(2H, m), 7.5-7.58(2H, m), 8.22(2H,m), 8.55(1H, br s), 8.9(1H, s), 10.65(1H, br s) 375 1H NMR (CD3OD):1.68-1.73(3H, d), 4.50(2H, s), 5.40-5.50(1H, 3.25 m), 6.7-6.8(1H, m),7.05-7.10(1H, m), 7.15-7.20(1H, d), 7.30-7.40(1H, t), 8.30-8.40(2H, m),8.45(1H, s), 8.50(1H, s) 376 455.00 1H NMR (CD3OD): 1.68-1.73(3H, d),2.75-2.80(3H, s), 3.38 4.50(2H, s), 5.40-5.50(1H, m), 6.8-6.9(1H, m),7.05-7.10(1H, m), 7.15-7.20(1H, d), 7.30-7.40(1H, t), 8.05-8.10(2H, m),8.20(1H, s), 8.60(1H, s) 377 469.00 1H NMR (CD3OD): 1.68-1.73(3H, d),2.15-2.20(2H, m), 3.29 2.90-2.95(6H, s), 3.10-3.20(2H, m), 4.05-4.10(2H,m), 5.50-5.60(1H, m), 6.8-6.9(1H, m), 7.05-7.10(1H, m), 7.15-7.20(1H,d), 7.30-7.40(1H, t), 8.20-8.24(1H, d), 8.25-8.30(2H, m), 8.60(1H, s)378 406.75 CDCl3 1.75(3H, d), 3.55(1H, s), 4.65(2H, s), 5.30-5.35(1H,3.15 m), 5.42-5.48(1Hm), 7.1-7.18(2H, m), 7.45-7.52(2H, m), 8.1-8.18(2H,m), 8.45(1H, br s), 8.78(1H, s), 9.4(1H, brs) 379 347.47 1H NMR(CDCl3/MeOD): 0.83(2H, m), 1.94(1H, m), 3.54 2.32(1H, m), 3.00(1H, m),3.30(1H, m), 3.36(2H, m), 3.46(1H, m), 3.60(1H, m), 3.87(1H, m),8.15(1H, s), 8.24(1H, s), 8.29(1H, s), 8.68(1H, s) 380 333.51 1H NMR(DMSO-d6): 2.15(1H, m), 2.30(2H, m), 3.35(2H, 5.00 m), 3.58(1H, m),4.77(1H, m), 7.87(1H, s), 8.29(3H, m), 8.81(1H, s), 8.94(2H, br s),12.45(1H, s) 381 333.40 1H NMR (DMSO-d6): 2.17(1H, m), 2.34(1H, m),3.34(3H, 5.00 m), 3.58(1H, m), 4.79(1H, m), 7.87(1H, d), 8.27(3H, m),8.68(1H, s), 8.81(2H, br s), 12.45(1H, s) 382 302.37 1H NMR (DMSO-d6):3.16(1H, s), 4.29(2H, m), 8.29(4H, 3.22 m), 8.88(1H, s), 12.40(1H, s)383 403.48 1H NMR (DMSO-d6): 0.82(2H, m), 1.11(1H, m), 1.22(1H, 3.18 m),1.85(2H, t), 1.98(3H, s), 2.07(1H, br s), 3.00(1H, t), 3.51(1H, s),3.83(1H, m), 4.40(1H, d), 8.40(1H, s), 8.44(1H, d), 8.65(1H, s),8.88(1H, s), 9.20(1H, br s), 12.91(1H, s) 384 420.80 CDCl3 1.72(3H, d),3.55(3H, s), 4.45(2H, s), 5.32-5.36(1H, 3.59 m), 5.47-5.53(1H, m),7.05-7.1(2H, m), 7.45-7.5(2H, m), 8.15(2H, m), 8.5(1H, br s), 8.85(1H,s), 10.05(1H, br s) 385 391.00 1H NMR (CD3OD): 1.15-1.20(9H, s),2.80(3H, s), 4.70-4.75(1H, 3.50 s), 8.05-8.10(1H, m), 8.12-8.15(2H, m),8.85(1H, s) 386 396.53 1H NMR (DMSO): 1.18(3H, t), 1.55(3H, d), 2.56(2H,3.88 q), 5.51(1H, m), 7.07-7.15(3H, m), 7.52(2H, m), 7.98(1H, s),8.14(1H, s), 8.23(1H, d), 8.60(1H, d), 12.22(1H, s) 387 365.00 (d6-DMSO,400MHz) 2.61(3H, d), 3.82-3.83(2H, m), 2.55 4.60(1H, dd), 5.02(1H, t),7.32(1H, d), 8.05(1H, d), 8.20(1H, s), 8.24(1H, d), 8.27(1H, d),8.66(1H, d), 12.36(1H, brs) 388 379.00 (d6-DMSO, 400MHz) 2.61(3H, d),3.30(3H, s), 3.74(2H, 2.82 brs), 4.82(1H, dd), 7.54(1H, d), 8.13(1H, d),8.23(2H, brs), 8.27(1H, s), 8.66(1H, s), 12.36(1H, brs) 389 441.00 1HNMR (CD3OD): 1.68-1.73(3H, d), 2.80-2.85(3H, s), 2.68 3.10-3.25(2H, m),3.35-3.55(2H, m), 4.55-4.60(1H, m), 8.10(1H, m), 8.15(1H, s), 8.20(1H,s), 8.75(1H, s) 390 453.00 1H NMR (CD3OD): 1.68-1.73(3H, d),2.10-2.50(2H, m), 1.74 2.90-3.20(4H, m), 4.50-4.60(2H, m), 8.10-8.15(2H,m), 8.20(1H, s), 8.80(1H, s) 391 379.00 1H NMR (CD3OD): 1.68-1.73(3H,d), 3.35-3.40(2H, m), 2.63 3.50-3.60(2H, m), 4.60-4.70(1H, m), 8.10(1H,m), 8.15(1H, s), 8.20(1H, s), 8.80(1H, s) 392 393.00 1H NMR (CD3OD):1.68-1.73(3H, d), 3.15-3.20(3H, s), 2.80 3.30-3.60(4H, m), 4.60-4.70(1H,m), 8.10(1H, m), 8.15(1H, s), 8.20(1H, s), 8.80(1H, s) 393 391.00(d6-DMSO, 400MHz) 0.89(3H, d), 0.94(3H, d), 1.58-1.81(3H, 3.33 m),2.60(3H, d), 4.61-4.67(1H, m), 7.59(1H, d), 8.03(1H, d), 8.21(1H, d),8.22(1H, s), 8.27(1H, d) 8.68(1H, d), 12.36(1H, s) 394 (400MHz, DMSO)1.56(3H, d), 5.41-5.48(1H, m), 7.15(2H, t), 7.56(2H, dd), 8.17(1H, d),8.21(1H, d), 8.28(1H, s), 8.64(1H, d), 8.84(1H, d), 12.75(1H, brs). 395367.00 (400MHz, DMSO) 1.50(3H, d), 5.10-5.14(1H, m), 6.32 2.50(1H, d),6.99(1H, d), 7.08-7.14(3H, m), 7.34(1H, t), 7.46-7.49(2H, m), 8.14(1H,s), 8.20(1H, d), 8.64(1H, s), 12.11(1H, brs)., MeOD-D4: 8.35(m, 2H);8.1(s, 1H); 7.95(dd, 1H); 7.5(m, 2H); 7.2(d, 1H); 7.15(m, 2H); 6.8(d,1H); 5.0(m, 1H); 1.65(d, 3H). 396 (400MHz, DMSO) 1.60(3H, d), 3.88(3H,s), 7.15(2H, t), 7.46-7.49(2H, m), 7.98(1H, d), 8.25-8.30(2H, m),8.34(1H, d), 8.56(1H, s), 12.65(1H, brs). 397 (400MHz, DMSO) 1.51(3H,s), 5.31-5.36(1H, m), 7.12(2H, t), 7.41-7.46(3H, m), 7.80-8.08(2H, m),8.17(1H, d), 11.98(1H, brs). 398 (400MHz, DMSO)1.51(3H, d),5.33-5.38(1H, m), 7.14(2H, t), 7.42-7.45(2H, m), 7.70-7.76(3H, m),7.88(1H, d), 8.21(1H, s), 12.20(1H, brs). 399 339.00 DMSO D62.78-2.92(4H, m), 3.50-3.62(4H, m), 7.05(1H, 1.24 s), 7.54(1H, s),8.27(1H, s), 8.45(1H, s), 8.68(1H, s) 400 403.00 (d6-DMSO, 400MHz)3.90-3.95(2H, m), 4.12(2H, d), 2.93 7.97(1H, t), 8.15(1H, s), 8.24(1H,d), 8.27(1H, d), 8.63(1H, d), 8.75(1H, t), 12.34(1H, brs) 401 350.00 NMR(DMSO) 1.3(3H, d, CH3), 2.6-2.8(2H, m, CH2), 2.59 4.65(H, m, alpha),7.15(H, m, ar), 8.15(H, m, ar), 8.25(2H, s, ar), 8.7(H, s, NH),12.1-12.5(2H, NH and COOH, brs × 2) 402 363.00 NMR (DMSO) 1.25(3H, d,CH3), 1.75(3H, m, CH3), 3.0(2H, 2.90 CH2, m), 4.65(H, m, alpha), 7.5(H,d, ar), 8.0(H, m, NH), 8.1(H, d, ar), 8.15(H, s, ar), 8.25(H, s, ar),8.7(H, s, NH) and 12.45(H, s, NH). 403 379.38 1H NMR (DMSO-d6): 1.73(2H,m), 1.99(2H, m), 2.84(2H, 2.21 m), 4.55(1H, m), 7.74(2H, br s), 7.95(1H,d), 8.19(1H, s), 8.28(2H, m), 8.73(1H, s), 12.38(1H, s), 12.99(1H, br s)404 418.49 1H NMR (DMSO-d6): 1.74(3H, m), 5.82(1H, m), 7.20(2H, 3.85 m),7.61(2H, m), 7.70(1H, s), 7.84(1H, s), 7.99(1H, s), 8.39(1H, s),8.54(1H, s), 8.66(1H, s), 8.79(1H, br s), 9.82(1H, br s), 13.08(1H, brs) 405 344.00 2.82-2.88(4H, m), 3.47-3.52(4H, m), 4.50(2H, s), 5.31(1H,2.34 br s), 6.61(1H, s), 7.15(1H, s), 8.20(1H, s), 8.25(1H, s), 8.70(1H,s), 12.25(1H, br s) 406 417.00 1H NMR (CD3OD): 1.1-1.4(6H, m),1.6-2.0(7H, m), 3.0-3.15(1H, 3.37 m), 3.65-3.80(1H, m), 5.6-5.7(1H, m),8.15(1H, m), 8.20-8.25(2H, m), 8.80(1H, s) 407 429.00 1H NMR (DMSO-d6):1.45-1.50(3H, d), 3.80-4.00(5H, 3.13 m), 4.60-4.65(1H, m), 6.80-6.85(1H,m), 7.95(1H, s), 8.10(1H, s), 8.25(1H, s), 8.70(2H, m), 12.2(1H, s) 408443.00 1H NMR (DMSO-d6): 1.37-1.47(6H, m), 3.85-4.05(2H, 3.33 m),4.10-4.20(2H, qd), 4.60-4.65(1H, m), 6.65-6.70(1H, d), 7.95(1H, s),8.10(1H, s), 8.25(1H, s), 8.70-8.80(2H, m), 12.2(1H, s) 409 342.80 DMSOD6 3.22-3.30(4H, m), 3.86-3.91(4H, m), 7.22(1H, 2.80 s), 7.69(1H, s),8.33(1H, s), 8.46(1H, s), 8.68(1H, s), 10.07(1H, s), 12.48(1H, s) 410457.00 1H NMR (DMSO-d6): 1.35-1.40(6H, m), 1.45-1.50(3H, 3.46 d),3.80-4.10(2H, m), 4.60-4.65(2H, m), 6.50-6.60(1H, m), 7.95(1H, s),8.10(1H, s), 8.25(1H, s), 8.70-8.80(2H, m), 12.5(1H, s) 411 423.00 1HNMR (DMSO-d6): 1.45-1.50(3H, d), 3.80-4.00(2H, 3.22 m), 4.50-4.60(1H,m), 4.75(1H, s), 8.05(1H, m), 8.30-8.40(2H, m), 8.50-8.60(1H, m),8.95-9.000(1H, m), 9.20(1H, m), 12.5(1H, s) 412 338.70 DMSO D62.80-2.90(4H, m), 3.48-3.61(4H, m), 4.43(1H, 3.16 s), 6.66(1H, s),7.25(1H, s), 8.27(1H, s), 8.35(1H, s), 8.66(1H, s), 12.28(1H, br s). 413399.00 1H NMR (CD3OD): 1.5-1.6(3H, d), 3.85-4.10(2H, m), 2.934.60-4.75(1H, m), 6.40-6.50(1H, s), 8.15(1H, d), 8.20-8.25(2H, m),8.90(1H, s) 414 497.00 1H NMR (CD3OD): 1.5-1.6(3H, d), 3.00-3.10(3H, s),3.08 3.30-3.60(6H, brm), 3.90-4.05(2H, m), 4.45-4.55(1H, m),6.50-6.60(1H, s), 8.20(1H, s), 8.30(1H, s), 8.50(1H, s), 8.70-8.80(1H,m) 415 583.00 1H NMR (DMSO-d6): 1.30-1.35(3H, d), 1.40(9H, s), 3.693.35-3.40(4H, m), 3.65-3.72(4H, m), 3.9-4.0(2H, m), 4.40-4.50(1H, m),6.35-6.40(1H, s), 7.10-7.20(1H, m), 8.15(1H, s), 8.25(1H, s), 8.50(1H,s), 8.60-8.70(1H, m), 12.5(1H, s) 416 483.00 1H NMR (CD3OD):1.50-1.60(3H, d), 3.40-3.45(4H, m), 2.73 3.95-4.05(2H, m), 4.10-4.20(2H,m), 4.6-4.7(1H, m), 6.55(1H, s), 8.35(1H, s), 8.40(2H, m), 8.90(1H, s)417 458.00 1H NMR (CD3OD): 1.40-1.50(3H, d), 3.50-3.55(2H, m), 2.883.75-3.85(2H, m), 3.95-4.05(2H, m), 4.10-4.20(2H, m), 4.45-4.55(1H, m),6.30-6.35(1H, s), 8.00-8.05(1H, s), 8.25(2H, m), 8.75(1H, s) 418 467.741H NMR (DMSO-d6): 1.43(3H, d), 3.93(2H, m), 4.56(1H, 3.35 m), 8.04(1H,s), 8.35(1H, d), 8.39(1H, d), 8.57(1H, m), 8.66(1H, m), 8.99(1H, s),12.67(1H, s) 419 485.00 1H NMR (CDCl3): 1.50-1.55(3H, d), 2.25-2.30(6H,s), 2.82 2.5-2.7(2H, m), 3.50-3.60(2H, m), 3.80-4.10(2H, m),4.50-4.60(1H, m), 5.55-5.60(1H, m), 5.90(1H, s), 7.60-7.90(2H, m),8.20(1H, s), 8.45-8.55(1H, brs), 10.5-10.8(1H, brs) 420 424.80 1H NMR(DMSO): 1.44(3H, d), 3.91(2H, m), 4.58(1H, 3.12 m), 8.38(1H, m),8.66-8.72(3H, m), 9.20(1H, d) 421 453.77 1H NMR (DMSO-d6): 3.92(2H, m),4.06(2H, s), 8.06(1H, 3.22 s), 8.33(1H, d), 8.44(1H, s), 8.59(2H, m),8.95(1H, s), 12.76(1H, s) 422 413.02 1H NMR (DMSO): 1.68(3H, d),5.67(1H, m), 7.19(2H, 3.90 m), 7.61(2H, m), 8.32(1H, s), 8.47(2H, m),8.85(1H, m), 9.18(1H, s), 12.83(1H, br s) 423 383.76 1H NMR (DMSO):1.65(2H, m), 5.56(1H, m), 5.75(1H, 3.45 br s), 7.22(2H, m), 7.50(2H, m),7.56(1H, s), 8.35(2H, s), 8.39(1H, m), 12.75(1H, br s), 13.5(1H, s) 424481.00 1H NMR (DMSO-d6): 1.45-1.50(3H, d), 3.05-3.20(3H, 3.67 m),3.80-4.00(2H, m), 5.30-5.50(1H, m), 8.00-8.10(1H, m), 8.30-8.40(1H, m),8.50-8.80(2H, m), 12.5(1H, s) 425 439.81 1H NMR (DMSO): 1.52(3H, d),2.99(6H, m), 5.36(1H, 3.56 m), 6.43(1H, br s), 7.16(2H, m), 7.49(2H, m),8.11(1H, m), 8.22(2H, m), 8.51(1H, br s), 12.36(1H, s) 426 478.00 1H NMR(DMSO-d6): 1.28(9H, s), 1.40-1.50(3H, d), 3.23 2.90-3.15(4H, m),4.50-4.60(1H, m), 6.70-6.80(1H, m), 7.60-7.65(1H, d), 8.08-8.13(1H, m),8.15-8.20(2H, m), 8.25(1H, m), 8.70(1H, s), 12(1H, s) 427 435.82 1H NMR(DMSO-d6): 3.92(2H, m), 4.24(2H, s), 7.43(1H, 3.28 m), 7.59(1H, m),7.77(2H, m), 8.22(2H, s), 8.78(1H, m), 8.81(1H, m), 8.92(1H, s),12.35(1H, s) 428 293.63 1H NMR (DMSO-d6): 1.25(3H, t), 2.93(2H, q),8.34(1H, 3.28 s), 8.37(1H, s), 8.57(1H, s), 8.07(1H, s), 12.84(1H, br s)429 441.00 1H NMR (CD3OD): 1.30-1.50(6H, dd), 1.60-1.70(3H, d), 3.453.05-3.15(1H, m), 3.85-4.05(2H, m), 4.80-4.90(1H, m), 8.10(1H, s),8.20-8.25(2H, m), 8.80(1H, s) 430 359.00 1H NMR (CD3OD): 1.30-1.40(6H,d), 2.88(3H, s), 2.95-3.05(1H, 3.00 m), 4.20-4.25(2H, m), 8.05(1H, s),8.20-8.25(2H, m), 8.80(1H, s) 431 378.73 1H NMR (CD3OD): 1.70-1.75(3H,d), 2.90-3.15(2H, m), 2.54 3.5-3.6(2H, m); 3.80-3.85(1H, m),8.35-8.45(3H, m), 8.60-8.70(1H, m) 432 470.19 1H NMR (CD3OD):1.30-1.40(6H, d), 1.60(3H, d), 2.95(3H, 3.43 s), 3.85-4.20(2H, m),4.80-4.90(1H, qd), 7.60(1H, s), 8.05(1H, s), 8.20(1H, s) 433 439.00 1HNMR (CD3OD): 1.45-1.55(3H, d), 1.80-1.90(2H, m), 3.33 2.65-2.80(2H, m);4.50-4.60(1H, m), 7.00-7.10(5H, m), 8.10-8.20(3H, m), 8.80(1H, s) 434443.00 1H NMR (CD3OD): 1.65-1.75(3H, d), 2.90-2.95(2H, m), 2.773.50-3.60(2H, m); 3.70-3.80(3H, m), 4.90-5.00(1H, m), 7.30(1H, s),8.40-8.45(2H, m), 8.50(1H, s), 8.60(1H, s), 8.80(1H, s) 435 448.00 1HNMR (CD3OD): 1.75-1.85(3H, d), 3.05-3.15(2H, m), 2.81 3.25-3.30(2H, m);3.45-3.55(2H, m), 3.60-3.80(4H, m), 3.90-4.00(2H, m), 4.95-5.00(1H, m),8.40-8.45(2H, m), 8.50(1H, s), 8.60(1H, s) 436 432.00 1H NMR (CD3OD):1.75-1.85(3H, d), 2.90-2.10(4H, m), 2.64 3.00-3.10(2H, m); 3.20-3.30(2H,m), 3.55-3.75(4H, m), 4.95-5.00(1H, m), 8.40-8.45(2H, m), 8.50(1H, s),8.60(2H, s) 437 478.19 1H NMR (CD3OD): 1.65-1.70(3H, d), 2.90-3.00(2H,m), 3.18 3.50-3.70(2H, m), 4.80-4.90(1H, m), 6.80-6.90(1H, t),6.95-7.05(3H, m), 7.20-7.25(1H, d), 7.35-7.40(1H, d), 8.35-8.40(3H, m),8.50(1H, m) 438 440.00 1H NMR (CD3OD): 1.65-1.70(3H, d), 3.70-3.90(4H,m), 2.93 4.80-4.90(1H, m), 7.80-7.85(1H, t), 7.90-7.95(1H, t),8.35-8.45(3H, m), 8.50(2H, s), 8.60(1H, m) 439 446.00 1H NMR (CD3OD):1.75-1.85(3H, d), 1.90-2.10(6H, m), 2.59 2.80-2.90(2H, m); 3.00-3.10(2H,m), 3.40-3.75(4H, m), 4.95-5.00(1H, m), 8.40-8.45(2H, m), 8.50(1H, s),8.60(2H, s) 440 435.14 1H NMR (CD3OD): 1.00-1.05(6H, d), 1.75-1.85(3H,d), 3.15 3.20-3.40(5H, m), 4.60-4.70(1H, m), 8.10-8.30(3H, m), 8.80(1H,s) 441 447.00 1H NMR (CD3OD): 1.75-1.85(3H, d), 3.10-3.80(8H, m), 2.664.95-5.00(1H, m), 8.40-8.45(2H, m), 8.50(1H, s), 8.60(1H, s) 442 443.001H NMR (CD3OD): 1.75-1.85(3H, d), 2.05-2.15(2H, m), 2.75 3.55-3.60(1H,m); 3.75-3.80(1H, m), 4.10-4.20(2H, m), 4.95-5.00(1H, m), 7.50(2H, s),8.35(1H, s), 8.40-8.60(3H, m), 8.63(1H, s), 8.87(1H, s) 443 428.00 1HNMR (CD3OD): 1.60-1.70(3H, d), 3.40-3.50(1H, m), 3.16 3.70-3.80(1H, m);4.00-4.05(2H, m), 4.80-4.90(1H, m), 5.90(1H, s), 6.60(1H, s),8.35-8.55(7H, m), 8.6(2H, s), 444 420.09 1H NMR (DMSO-d6): 1.26(3H, d),1.68(3H, s), 3.05(4H, 2.68 m), 4.54(1H, m), 7.78(2H, m), 8.13(1H, s),8.27(3H, m), 8.66(1H, s), 12.40(1H, s) 445 470.12 1H NMR (CDC13+CD3ODdrops): 1.19(5H, m), 1.66(3H, 2.88 d), 2.76(2H, m), 3.06(2H, m),4.69(1H, m), 8.10(1H, s), 8.18(1H, s), 8.30(1H, s), 8.64(1H, s) 446518.19 1H NMR (CDC13+CD3OD drops): 2.83(2H, t), 3.33(1H, 2.88 s),3.40(1H, m), 3.58(1H, m), 4.05(2H, m), 4.59(1H, m), 6.94(1H, br s),7.06(2H, d), 7.56(2H, d), 7.92(1H, s), 8.03(1H, s), 8.12(1H, s),8.12(1H, s), 8.71(1H, s) 447 423.00 1H NMR (CD3OD): 1.05-1.10(3H, t),1.60-1.70(3H, d), 3.23 2.35-2.40(2H, m), 2.45-2.55(2H, m); 3.40-3.50(2H,m), 4.55-4.60(1H, m), 8.10(1H, s), 8.15(1H, s), 8.20(1H, s), 8.80(1H, s)448 446.00 1H NMR (CD3OD): 1.60-1.70(4H, m), 1.90-2.05(2H, m), 2.622.10-2.20(1H, m), 2.25-2.40(1H, m); 2.70-2.80(3H, m), 2.90-3.00(1H, m),3.05-3.10(1H, m), 3.35-3.45(2H, m), 3.50-3.60(2H, m), 3.65-3.75(2H, m),4.90-5.00(1H, m), 8.35-8.40(2H, m), 8.50(1H, s), 8.60-8.65(1H, s) 449440.00 1H NMR (CD3OD): 1.65-1.70(3H, d), 3.70-3.90(4H, m), 2.904.80-4.90(1H, m), 7.80-7.85(1H, t), 8.35-8.45(3H, m), 8.45-8.55(2H, s),8.60(1H, s), 8.75(1H, s) 450 452.00 (d6-DMSO, 400MHz) 1.36(3H, d),2.28(3H, s), 2.78(3H, 2.76 s), 2.79-2.99(2H, m), 3.15-3.25(2H, m),4.50(1H, brs), 6.22(1H, brs), 7.05(1H, brs), 7.38(1H, d), 8.13(1H, brs),8.22(1H, s), 8.26(1H, d), 8.77(1H, brs), 12.30(1H, s) 451 492.00 1H NMR(CD3OD): 1.40-1.45(9H, s), 1.65-1.70(3H, d), 3.42 2.80-2.85(3H, m),2.95-3.00(1H, m), 3.05-3.10(1H, m), 3.40-3.50(2H, m), 4.60-4.70(1H, m),8.15(1H, s), 8.25(1H, s), 8.30(1H, s), 8.80(1H, s) 452 392.00 1H NMR(CD3OD): 1.65-1.70(3H, d), 3.20-3.40(2H, m), 2.59 3.70(3H, s),3.75-3.80(2H, m), 4.50-4.60(1H, m), 6.25-6.30(1H, d), 6.35-6.40(1H, t),6.55-6.65(2H, m), 7.90(1H, s), 8.05(1H, s), 8.15(1H, s), 8.55(1H, s) 453485.00 1H NMR (CD3OD): 1.65-1.70(3H, d), 3.20-3.40(2H, m), 3.13 3.70(3H,s), 3.75-3.80(2H, m), 4.50-4.60(1H, m), 6.25-6.30(1H, d), 6.35-6.40(1H,t), 6.55-6.65(2H, m), 7.90(1H, s), 8.05(1H, s), 8.15(1H, s), 8.55(1H, s)454 484.00 1H NMR (CD3OD): 1.08-1.13(6H, m), 1.55-1.60(3H, d), 2.942.85-3.05(2H, m), 3.10-3.25(2H, m), 3.35-3.40(1H, m), 4.60-4.70(1H, m),8.10(1H, s), 8.15(1H, s), 8.20(1H, s), 8.80(1H, s) 455 468.00 (d6-DMSO,400MHz) 1.39(3H, brs), 2.70-2.96(5H, m), 2.96 3.16-3.26(2H, m), 3.84(3H,s), 4.31-4.36(1H, m), 6.60(1H, s), 7.03(1.4H, brs), 7.43(0.6H, brs),8.01(1H, t), 8.26(1H, s), 8.41(1H, s), 8.70(0.4H, brs), 9.09(0.6H, brs),12.39(1H, s) 456 420.00 (d6-DMSO, 400MHz) 1.81-1.88(1H, m),1.94-1.98(1H, 2.90 m), 2.15(6H, s), 2.24-2.28(1H, m), 2.38-2.44(1H, m),2.86(3H, s), 3.23(3H, s), 5.38-5.40(1H, m), 7.83(1H, d), 8.15(1H, s),8.20(1H, d), 8.28(1H, d), 8.72(1H, d), 12.35(1H, s) 457 455.13 1H NMR(DMSO): 1.47(3H, d), 3.36(1H, m), 3.51(1H, 3.29 m), 3.80(2H, m),6.64(2H, d), 6.82(1H, t), 7.09(2H, t), 8.07(1H, br s), 8.28(4H, m),8.66(1H, s), 12.50(1H, s) 458 512.22 1H NMR (DMSO): 1.45(3H, d),3.07(4H, m), 4.55(1H, 3.34 m), 4.93(2H, m), 7.21(1H, m), 7.29(5H, m),8.01(1H, br s), 8.17(1H, m), 8.28(3H, m), 8.65(1H, s), 12.44(1H, s) 459479.16 1H NMR (DMSO+CD3OD drops): 1.41(3H, d), 3.27(2H, 3.09 m),3.58(1H, m), 3.60(1H, m), 4.53(1H, m), 7.42(2H, m), 7.60(2H, m),8.13(1H, s), 8.24(2H, m), 8.43(1H, s), 8.51(1H, s) 460 460.17 1H NMR(DMSO): 1.48(5H, m), 1.75(2H, m), 2.10(2H, 2.86 t), 2.92(2H, m),3.05(4H, m), 4.53(1H, m), 7.90(1H, br s), 8.04(1H, m), 8.28(3H, m),8.66(1H, s), 12.41(1H, s) 461 388.04 1H NMR (DMSO): 1.46(3H, d),2.59(2H, m), 3.35(1H, 2.84 m), 4.57(1H, m), 7.95(1H, br s), 8.23(1H, s),8.28(2H, s), 8.47(1H, t), 8.65(1H, s) 462 555.18 1H NMR (DMSO): 1.45(3H,d), 2.60(2H, m), 3.26(2H, 3.59 m), 3.85(2H, d), 4.56(1H, m), 7.22(1H,t), 7.37(2H, d), 7.69(1H, d), 8.21(4H, m), 8.66(1H, s), 12.31(1H, s) 463419.00 1H NMR (CD3OD): 0.70-0.75(3H, t), 1.05-1.15(7H, m), 3.501.35-1.45(2H, m), 1.55-1.60(3H, d), 3.90-4.00(1H, m), 4.60-4.65(1H, m),8.10(1H, s), 8.15(1H, s), 8.20(1H, s), 8.80(1H, s) 464 405.00 1H NMR(CD3OD): 0.70-0.75(6H, t), 1.30-1.40(2H, m), 3.40 1.40-1.50(1H, m),1.55-1.60(3H, d), 2.90-3.00(1H, m), 3.15-3.20(1H.m), 4.70-4.75(1H, m),8.10(1H, s), 8.15(1H, s), 8.20(1H, s), 8.80(1H, s) 465 391.00 1H NMR(CD3OD): 0.70-0.75(3H, t), 1.05-1.10(3H, d), 3.30 1.35-1.45(2H, m),1.55-1.60(3H, d), 3.80-3.90(1H, m), 4.70-4.75(1H, m), 8.10(1H, s),8.15(1H, s), 8.20(1H, s), 8.80(1H, s) 466 407.00 1H NMR (CD3OD):1.55-1.60(3H, d), 2.40-2.50(2H, m), 2.50 3.35-3.55(2H.m), 4.65-4.70(1H,m), 8.25(1H, s), 8.30-8.40(2H, m), 8.70(1H, s) 467 420.00 1H NMR(CD3OD): 1.55-1.60(3H, d), 2.30-2.40(2H, m), 2.80 3.35-3.60(5H, m),4.60-4.70(1H, m), 8.15(1H, s), 8.20(1H, s), 8.25(1H, s), 8.80(1H, s) 468448.00 1H NMR (CD3OD): 1.00-1.10(6H, m), 1.55-1.60(3H, d), 3.002.30-2.40(2H, m), 3.35-3.50(3H, m), 3.80-3.90(2H, m), 4.60-4.70(1H, m),8.15(1H, s), 8.20(1H, s), 8.25(1H, s), 8.80(1H, s) 469 484.00 1H NMR(CD3OD): 0.90-1.00(6H, m), 1.55-1.60(3H, d), 3.00 2.95-3.05(1H, m),3.10-3.25(2H.m). 3.50-3.60(1H.m), 3.70-3.80(1H, m), 4.65-4.70(1H, m),8.10(1H, s), 8.30-8.40(2H, m), 8.70(1H, s)

B) Biological Data:

Example 1 JAK3 Inhibition Assay

Compounds were screened for their ability to inhibit JAK3 using astandard radioactive enzyme assay. 1.5 μL/well of a DMSO stockcontaining serial dilutions of a compound of the present invention(concentrations ranging from 667 μM to 46 nM) was placed in a 96 wellpolycarbonate plate. 50 μL per well of kinase buffer (100 mM HEPES (pH7.4), 10 mM MgCl₂, 25 mM NaCl, 1 mM DTT, and 0.01% bovine serum albumin(BSA)) containing 2 μM poly(Glu)₄Tyr and 10 μM ATP was also added to theplate. To initiate the reaction, 50 μL kinase buffer containing 2 nMJAK3 enzyme was added. Final ATP concentration was 5 μM [γ-³³P] ATP (200μCi ³³P ATP/μmol ATP (Perkin Elmer, Cambridge, Mass.). After 20 minutesat room temperature (25° C.), the reaction was stopped by adding 50 μL20% trichloroacetic acid (TCA)/0.4 mM ATP to each well. The entirecontent of each well was then transferred to a 96 well glass fiberfilter plate using a TomTek Cell Harvester. After washing, 60 μLscintillation fluid was added and ³³P incorporation detected using aPerkin Elmer TopCount. After removing mean background values for all ofthe data points the data was fit using Prism software to obtain aK_(i)(app). Inhibition of JAK2 was measured as above except that finalpoly(Glu)₄Tyr concentration was 15 μM and final ATP concentration was 12μM.

Example 2 ROCK Inhibition Assays

Compounds were screened for their ability to inhibit ROCK I (AA 6-553)activity using a standard coupled enzyme system (Fox et al. (1998)Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 2 mM DTT and1.5% DMSO. Final substrate concentrations in the assay were 45 μM ATP(Sigma Chemicals, St Louis, Mo.) and 200 μM peptide (American Peptide,Sunnyvale, Calif.). Reactions were carried out at 30° C. and 45 nM ROCKI. Final concentrations of the components of the coupled enzyme systemwere 2.5 mM phosphoenolpyruvate, 350 μM NADH, 30 μg/ml pyruvate kinaseand 10 μg/ml lactate dehydrogenase.

Some compounds were screened for their ability to inhibit ROCK using astandard radioactive enzyme assay. Assays were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 2 mM DTT, and1.5% DMSO. Final substrate concentrations in the assay were 13 μM[γ-³³P] ATP (25 mCi ³³P ATP/mmol ATP, Perkin Elmer, Cambridge,Mass./Sigma Chemicals, St Louis, Mo.) and 27 μM Myelin Basic Protein(MBP). Final enzyme concentration in the assay was 5 nM ROCK. Assayswere carried out at room temperature. 1.5 μl of DMSO stock containingserial dilutions of the compound of the present invention(concentrations ranging from 10 μM to 2.6 nM) was placed in a 96 wellplate. 50 μl of Solution 1 (100 mM HEPES (pH 7.5), 10 mM MgCl₂, 26 mM[γ-³³P] ATP) was added to the plate. The reaction was initiated byaddition of 50 μl of Solution 2 (100 mM HEPES (pH 7.5), 10 mM MgCl₂, 4mM DTT, 54 mM MBP and 10 nM ROCK). After 2 hours the reaction wasquenched with 50 μL of 30% trichloroacetic acid (TCA, Fisher) containing9 mM ATP. Transfer of 140 μL of the quenched reaction to a glass fiberfilter plate (Corning, Cat. No. 3511) was followed by washing 3 timeswith 5% TCA. 50 μL of Optima Gold scintillation fluid (Perkin Elmer) wasadded and the plates were counted on a Top Count (Perkin Elmer). Afterremoving mean background values for all of the data points the data wasfit using Prism software to obtain a K_(i)(app).

Example 3 Aurora Inhibition Assay

Compounds were screened for their ability to inhibit full lengthAurora-A (AA 1-403) activity using a standard coupled enzyme system (Foxet al., Protein Sci., 7, pp. 2249 (1998)). Reactions were carried out ina solution containing 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl,300 μM NADH, 1 mM DTT and 3% DMSO. Final substrate concentrations in theassay were 200 μM ATP (Sigma Chemicals, St Louis, Mo.) and 800 μMpeptide (LRRASLG, American Peptide, Sunnyvale, Calif.). Reactions werecarried out at 30° C. and 35 nM Aurora-A. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,200 μM NADH, 60 μg/ml pyruvate kinase and 20 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer solution (60 μl) was incubated in a 96well plate with 2 μl of the test compound of interest at finalconcentrations spanning 0.002 μM to 30 μM at 30° C. for 10 min.Typically, a 12 point titration was conducted by preparing serialdilutions (from 1 mM compound stocks) with DMSO of the test compounds indaughter plates. The reaction was initiated by the addition of 5 μl ofATP (final concentration 200 μM). Rates of reaction were obtained usinga Molecular Devices Spectramax plate reader (Sunnyvale, Calif.) over 10min at 30° C. The Ki values were determined from the rate data as afunction of inhibitor concentration using computerized nonlinearregression (Prism 3.0, Graphpad Software, San Diego, Calif.). Aurora-Cactivity was screened in a similar manner using Aurora-C protein.Aurora-B activity was screened using a radioactive assay, such asdescribed in Examples 1 and 2, but using Aurora-B protein.

Table 5 below depicts enzyme inhibition data (K_(i)) for certainexemplary compound numbers correspond to those compounds depicted inTable 1.

Table 6 below depicts enzyme inhibition data (K_(i)) for certainexemplary compound numbers correspond to those compounds depicted inTable 2.

In Tables 5 and 6, “A” represents a K_(i) of less than 0.5 μM, “B”represents a K_(i) of between 0.5 and 5.0 μM, and “C” represents a K_(i)greater than 5.0 μM for the indicated enzyme. If more than one value ofK_(i) has been determined, the average K_(i) is indicated. If no valueis indicated, then the K_(i) was not determined. For ROCK, the term“Enzyme” indicates that an enzyme-linked assay was used; the term “³³P”indicates that a radioactive assay was used.

TABLE 5 Enzyme Inhibition Data for Compounds of Table 1 Compound ROCKNumber Aurora A JAK2 JAK3 Enzyme ³³P 1 A A 2 B A 3 A A A B 4 B A A 5 B CA 6 B B A 7 B A A A 8 B A A A 9 B B B B 10 A A A 11 A A A 12 A B B 13 BB A 14 A A A 15 A 16 A A A A 17 B A B B 18 B A A A 19 A A A 20 A A A 21A A 22 A 23 A 24 A 25 B A 26 B B B 27 A 28 A 29 A 30 A A 31 A A 32 B A A33 B A A A 34 A A A 35 B C B 36 B B B 37 A A A 38 B A A A 39 C C B 40 AA A 41 A A B 42 A A B 43 B A A A 44 B B B A 45 B B B 46 B A A 47 B B B48 B B B 49 B A B 50 B B B 51 B B A A 52 C C B 53 C B B 54 C C B 55 B BA

TABLE 6 Enzyme Inhibition Data for Compounds of Table 2 Compound AuroraAurora ROCK No. A B Aurora C JAK2 JAK3 Enzyme ³³P 1 A A B 2 A A B 3 A AA 4 A A A A 5 A A B 6 A A A 7 B B B 8 A A A A 9 A A B 10 A A A A 11 A AB 12 A A A 13 A A B 14 B A A A 15 B B B 16 A A A 17 B B A 18 B A A B B19 A A A A A 20 A A A B 21 A A A 22 A A A 23 B B A 24 B A A A 25 A A A A26 A A A 27 A A A 28 A A A 29 A A A 30 A A A A 31 A A A 32 A A A B 33 AA A A A 34 A A A B 35 A A A A A 36 A A A B B 37 A A B A 38 B A A B B 39A A A B 40 A A B 41 A A A B 42 A A A B 43 A B B B 44 A B B B 45 A A A B46 A A A B 47 B A A B 48 A A A B 49 B A A B 50 B A A A 51 B B B 52 B C CB 53 A A A A 54 A B B B 55 B B 56 B C B 57 B C B B 58 B A A B 59 B A A B60 B B B B 61 A A B 62 A A A 63 A A A 64 A A B 65 A A B 66 B A A B 67 AA A B 68 A A A B 69 B A A B 70 B A A B 71 A A B 72 A B A B 73 A A A 74 AA A 75 A A A A 76 A A A B 77 A A B 78 A A A B 79 A A A B 80 A A A B 81 AB B B 82 A A A 83 A A B 84 A A B 85 A A B 86 A A B 87 A A B 88 A A B 89A A B 90 A A B 91 B B B 92 A A A A 93 A A A B 94 B B B 95 B B B B 96 B AA B 97 A A A B 98 A A A B 99 A A A B 100 A A A B 101 A A A B 102 B A A B103 B A A B 104 A A B 105 A A B 106 A A B 107 A A B 108 A A B 109 A A B110 B B B B 111 A A B 112 A A B 113 B A A B 114 B A A B 115 A A B 116 AA B 117 B A A B 118 B A A B 119 B A A B 120 A A A B 121 B A A B 122 B AA B 123 B A A B 124 B A A B 125 B A A B 126 C B B 127 A A B 128 B A A B129 B A B 130 A A A B 131 A A A B 132 A A A B 133 A A B 134 A A B 135 AA A 136 A A A 137 A A B 138 A A B 139 A A B 140 A A B 141 A A B 142 B AB 143 B A B 144 A A B 145 A A B 146 A A B 147 A A B 148 B A A 149 A A B150 B A A B 151 A A A A 152 B A A B 153 B A A B 154 B A A B 155 B A A B156 B A A A 157 B A A B 158 B A A B 159 B A A B 160 A A B 161 B A A B162 B A A B 163 B A A B 164 B A A B 165 B A A B 166 B A A B 167 B A A B168 B A A B 169 B A A B 170 B A A B 171 A A B 172 B A A A 173 A A A 174A A 175 A A 176 A A 177 A A A B 178 B B B 179 B A A B 180 A A B 181 B AA B 182 B A A B 183 A A B 184 B A B 185 B A 186 A A A 187 B A 188 C B189 A A B 190 B A A B 191 B A A A 192 B A A A 193 A A A 194 A A B 195 BA B 196 C B B 197 B A B 198 C B B 199 B A B 200 B A B 201 A A B 202 B BB 203 A A B 204 A B 205 A B 206 A B 207 A B 208 A B 209 A B 210 B 211 AB 212 A B B 213 A B 214 B B 215 B B 216 A B 217 A B B 218 A A A 219 A BB 220 B B 221 A A 222 A A 223 B B 224 A A 225 B B 226 B 227 A A 228 A A229 A B 230 B B 231 A A 232 A B 233 B 234 A 235 A A 236 A 237 A A A B238 A A A B 239 A A 240 A B 241 B 242 A B A B 243 A B 244 B B 245 A 246B B 247 A B 248 A B 249 A B 250 A B 251 A B 252 A A B 253 A A 254 A B255 A A 256 A A 257 B B 258 A B 259 A A 260 A A B 261 B B 262 B B 263 AB 264 A B 265 A B 266 A B 267 A A 268 B 269 A 270 B B 271 A B 272 B 273A B 274 A B 275 B B 276 A B 277 A A 278 A A 279 B 280 A 281 A 282 A 283B 284 B B 285 A A A B 286 A B 287 A 288 A 289 A B 290 A B B B 291 A B B292 C B 293 B B 294 A B 295 A B 296 A B 297 A B 298 B B 299 A A A 300 AA A 301 B B 302 A A B 303 A 304 B 305 A A B 306 A A A B 307 A A 308 B B309 B B 310 A A B 311 A B 312 A A A B 313 A B 314 B 315 A B B 316 A A AB 317 A A A B 318 A B 319 B 320 A 321 A B A B 322 A A B 323 A A A B 324A A A B 325 A A A B 326 A A A A 327 A A A A 328 A A A B 329 A A A A 330A A B 331 A A B 332 A 333 A A A B 334 A 335 A A 336 A B 337 A B 338 A B339 A A A B 340 A A A B 341 A A B 342 A B 343 B 344 A A 345 A B B A 346B 347 A B B A 348 A A A B 349 A A A B 350 B 351 A B 352 A 353 B 354 A AB 355 A A A B 356 A A A B 357 A B 358 B 359 A A A B 360 B B 361 A A A B362 A A A B 363 A B 364 A B 365 A B 366 A B 367 A B 368 A A A B 369 A AA A B 370 A A A B 371 A A A A B 372 A B 373 A B 374 A A A B 375 A A B376 A B 377 A B 378 A B 379 A A 380 A A B 381 A A 382 A B 383 A B 384 AB 385 A A B 386 A A A A B 387 A A A B 388 A A B 389 A B 390 B B 391 A AA B 392 A B 393 A B 394 A B 395 A A A A B 396 A B 397 A A B 398 A B 399A A 400 A A B 401 A B 402 B B 403 B 404 A B B 405 A 406 A B B 407 A A B408 A B 409 A A 410 A B 411 A A B 412 A 413 A A B 414 B B B 415 A A B416 A B B 417 A A B 418 A A B 419 B B 420 A A A B 421 A B B 422 A A B423 A A B 424 A A B 425 A A B 426 A A B 427 A B B B 428 A B B 429 A B BB 430 A B B B 431 A A A B 432 B B B 433 B B B 434 B B B 435 B B B 436 BA B 437 A B B 438 B B B 439 A A B 440 B B B 441 B B B B 442 A B B B 443A A A A B 444 A A A B B 445 A B A 446 A A A B B 447 A B B B 448 B B B449 A B B 450 A A A B B 451 B B B 452 A A A B 453 B B B 454 A B B B 455A B B B 456 A B B 457 B B 458 A A A 459 B B 460 B B 461 A A A 462 B B463 A B 464 B 465 A 466 B 467 A 468 A 469 A

1. A compound of formula (IB):

or pharmaceutically acceptable salts thereof, wherein: R¹ is hydrogen;R² and R⁴ are each hydrogen; R³ is independently hydrogen or halogen; xis 1, 2 or 3; each occurrence of R⁵ is independently halogen, CN, NO₂,or U—R′, wherein at least one R⁵ is other than H; each U isindependently a bond or an optionally substituted C₁-C₆ alkylidenechain, wherein up to two methylene units of the chain are optionally andindependently replaced by —NR′—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—,—CONR′—, —NR′CO—, —NR′CO₂—, —SO₂NR′—, —NR′SO₂—, —CONR′NR′—, —NR′CONR′—,—OCONR′—, —NR′NR′—, —NR′SO₂NR′—, —SO— or —SO₂—; and each occurrence ofR′ is independently hydrogen or an optionally substituted group selectedfrom a C₁-C₆ aliphatic group, a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-12membered saturated, partially unsaturated, or fully unsaturated bicyclicring system having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two occurrences of R′, are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; wherein an optionalsubstituent on an unsaturated carbon atom of an aryl or heteroaryl groupis selected from halogen; —R^(o); —OR^(o); —SR^(o); phenyl (Ph)optionally substituted with R^(o); —O(Ph) optionally substituted withR^(o); —(CH₂)₁₋₂(Ph), optionally substituted with R^(o); —CH═CH(Ph),optionally substituted with R^(o); a 5-6 membered heteroaryl orheterocyclic ring optionally substituted with R^(o); —NO₂; —CN;—N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂;—NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o);—NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)CH₂C(O)R^(o);—CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂;—OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o))R^(o);—S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o);—C(═NH)—N(R^(o))₂; or —(CH₂)₀₋₂NHC(O)R^(o); wherein each independentoccurrence of R^(o) is selected from hydrogen, optionally substitutedC₁₋₆ aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclicring, phenyl, —O(Ph), or —CH₂(Ph), or, two independent occurrences ofR^(o), on the same substituent or different substituents, taken togetherwith the atom(s) to which each R^(o) group is bound, to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; wherein eachoptional substituent on the aliphatic group of R^(o) is selected fromNH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic,OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄ aliphatic, wherein each of the foregoingC₁₋₄aliphatic groups of R^(o) is unsubstituted; wherein an optionalsubstituent on a saturated carbon of an aliphatic or heteroaliphaticgroup, or on a saturated carbon of a non-aromatic heterocyclic ring isselected from halogen; —R^(o); —OR^(o); —SR^(o); phenyl (Ph) optionallysubstituted with R^(o); —O(Ph) optionally substituted with R^(o);—(CH₂)₁₋₂(Ph), optionally substituted with R^(o); —CH═CH(Ph), optionallysubstituted with R^(o); a 5-6 membered heteroaryl or heterocyclic ringoptionally substituted with R^(o); —NO₂; —CN; —N(R^(o))₂;—NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂;—NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o);—NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)CH₂C(O)R^(o);—CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂;—OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o))R^(o);—S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o);—C(═NH)—N(R^(o))₂; or —(CH₂)₀₋₂NHC(O)R^(o); ═O; ═S; ═NNHR*; ═NN(R*)₂;═NNHC(O)R*; ═NNHCO₂(alkyl); ═NNHSO₂(alkyl); or ═NR*; where each R* isindependently selected from hydrogen or a C₁₋₆ aliphatic group; whereinan optional substituent on a nitrogen of a non-aromatic heterocyclicring is selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)CH₂C(O)R⁺,—SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; whereinR⁺ is hydrogen, an optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted —O(Ph), optionallysubstituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionallysubstituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl orheterocyclic ring having one to four heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur; or, two independent occurrences of R⁺,on the same substituent or different substituents, taken together withthe atom(s) to which each R⁺ group is bound, form an optionallysubstituted 3-12 membered saturated, partially unsaturated, or fullyunsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; wherein anoptional substituent on the aliphatic group or the phenyl ring of R⁺ isselected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, halogen,C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C₁₋₄aliphatic), —O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), whereineach of the foregoing C₁₋₄aliphatic groups of R⁺ is unsubstituted;provided that: if R³ is H and x is 1, then R⁵ is not —SMe, NH₂ or anoptionally substituted NH-piperidine.
 2. The compound of claim 1,wherein each occurrence of R⁵ is independently R′, —CH₂R′, halogen, CN,NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′,—NR′COR′, —NR′COCH₂R′, —NR′CO(CH₂)₂R′, —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂,—CONR′(CH₂)₂N(R′)₂, —CONR(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′,O(CH₂)₃R′, O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,—NR′CH(CH₂OH)R′, —NR′CH(CH₂CH₂OH)R′, —NR′(CH₂)R′, —NR′(CH₂)₂R′,—NR′(CH₂)₃R′, NR′(CH₂)₄R′, —NR′(CH₂)N(R′)₂, —NR′(CH₂)₂N(R′)₂,—NR′(CH₂)₃N(R′)₂, —NR′(CH₂)₄N(R′)₂, —NR′(CH₂)OR′, —NR′(CH₂)₂OR′,—NR′(CH₂)₃OR′, or —NR′(CH₂)₄OR′.
 3. A compound which is


4. The compound according to claim 1, wherein R³ is selected from H, Cl,or F.
 5. The compound according to claim 1, wherein each occurrence ofR⁵ is independently selected from R′, —CH₂R′, halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NR′COR′, —NR′COR⁸R′,—NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′R⁸N(R′)₂, —OR⁸OR′, —OR⁸N(R′)₂,—NR′CH(R⁹)R′, —NR′CH(R⁹)C(O)OR′, —N(R′)R⁸R′, —N(R′)R⁸R′, —N(R′)R⁸N(R′)₂,—N(R′)R⁸OR′, —NR′CH₂C(O)N(R′)₂, or —NR′CH(R⁹)C(O)N(R′)₂, wherein R⁸ isan optionally substituted C₁-C₄ alkyl and R⁹ is an optionallysubstituted C₁-C₆ aliphatic.
 6. The compound according to claim 1,wherein x is 2 or 3 and at least two R⁵ on adjacent ring members are R′,and wherein said two R⁵ taken together with the atoms to which they arebound to form an optionally substituted 3-12 membered saturated,partially saturated or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen orsulfur.
 7. A compound selected from the following: Cmpd No. (II-)Compound 237

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8. The compound of claim 1, wherein x is 1 or 2, and each occurrence ofR⁵ is independently halogen, R′, CN, —CH₂CN, —(CH₂)₂CN, NO₂, —CH₂NO₂,—(CH₂)₂NO₂, CON(R′)₂, —CH₂CON(R′)₂, —(CH₂)₂CON(R′)₂, COOR′, —CH₂COOR′,—(CH₂)₂COOR′, —SO₂N(R′)₂, —CH₂SO₂N(R′)₂, —(CH₂)₂SO₂N(R′)₂, —NR′SO₂R′,—CH₂NR′SO₂R′, —(CH₂)₂NR′SO₂R′, NR′CON(R′)₂, —CH₂NR′CON(R′)₂,—(CH₂)₂NR′CON(R′)₂, —NR′SO₂N(R′)₂, —CH₂NR′SO₂N(R′)₂,—(CH₂)₂NR′SO₂N(R′)₂, —COCOR′, —CH₂COCOR′, —(CH₂)₂COCOR′, —N(R′)₂,—CH₂N(R′)₂, —(CH₂)₂N(R′)₂, —OR′, —CH₂OR′, —(CH₂)₂OR′, —NR′COR′,—NR′COCH₂R′, —NR′CO(CH₂)₂R′, —CH₂NR′COR′, or —(CH₂)₂NR′COR′.
 9. Thecompound according to claim 5, wherein each occurrence of R⁵ isindependently selected from R′, —CH₂R′, halogen, —CN, —NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NR′COR′, —NR′COCH₂R′,—NR′CO(CH₂)₂R′, —NR′COOR′, —CON(R′)₂, —SO₂N(R′)₂, —CONR′(CH₂)₂N(R′)₂,—CONR(CH₂)₃N(R′)₂, —CONR′(CH₂)₄N(R′)₂, —O(CH₂)₂OR′, O(CH₂)₃OR′,O(CH₂)₄OR′, —O(CH₂)₂N(R′)₂, —O(CH₂)₃N(R′)₂, —O(CH₂)₄N(R′)₂,—NR′CH(CH₃)R′, NR′CH(CF₃)R′, —NR′CH(CH₃)C(O)OR′, —NR′CH(CF₃)C(O)OR′,—NR′(CH₂)R′, —NR′(CH₂)₂R′, —NR′(CH₂)₃R′, —NR′(CH₂)₄R′, —NR′(CH₂)N(R′)₂,—NR′(CH₂)₂N(R′)₂, —NR′(CH₂)₃N(R′)₂, —NR′(CH₂)₄N(R′)₂, —NR′(CH₂)OR′,—NR′(CH₂)₂OR′, —NR′(CH₂)₃OR′, —NR′(CH₂)₄OR′, —NR′CH(CH₂CH₃)R′,—NR′CH₂C(O)N(R′)₂, —NR′CH(CH₃)C(O)N(R′)₂, NR′CH(CF₃)C(O)N(R′)₂,—NR′CH(CH₂CH₃)C(O)N(R′)₂, —NR′CH(CH(CH₃)₂)C(O)N(R′)₂,—NR′CH(C(CH₃)₃)C(O)N(R′)₂, —NR′CH(CH₂CH(CH₃)₂)C(O)N(R′)₂, or—NR′CH(CH₂CH₂N(Me)₂)C(O)N(R′)₂.
 10. The compound according to claim 5,wherein at least one occurrence of R⁵ is independently selected from—NR′CH(CH₂OH)R′, —NR′CH(CH₂OMe)R′, —NR′CH(CH₂OEt)R′, —NR′CH(CH₂OCF₃)R′,—NR′CH(CH₂CH₂OH)R′, —NR′CH(CH₂CH₂OMe)R′, —NR′CH(CH₂CH₂OEt)R′,—NR′CH(CH₂CH₂OCF₃)R′, —NR′CH(CH₃)C(O)OR′, —NR′CH(CF₃)C(O)OR′,—NR′CH(CH₃)C(O)N(R′)₂, —NR′CH(CF₃)C(O)N(R′)₂, —NR′CH(CH₂CH₃)C(O)N(R′)₂,—NR′CH(CH₂OH)C(O)N(R′)₂, —NR′CH(CH₂OMe)C(O)N(R′)₂,—NR′CH(CH₂OEt)C(O)N(R′)₂ or —NR′CH(CH₂OCF₃)C(O)N(R′)₂, wherein R′ is anoptionally substituted C₁-C₄ aliphatic.
 11. The compound according toclaim 5, wherein at least one occurrence of R⁵ is selected fromNHCH₂C(O)NHR′, —NHCH(CH₃)C(O)NHR′, —NHCH(CH₂CH₃)C(O)NHR′,—NHCH(CH(CH₃)₂)C(O)NHR′, —NHCH(C(CH₃)₃)C(O)NHR′,—NHCH(CH₂CH(CH₃)₂)C(O)NHR′, —NHCH(CH₂OH)C(O)NHR′, —NHCH(CH₂OMe)C(O)NHR′or —NHCH(CH₂CH₂N(Me)₂)C(O)NHR′, wherein R′ is an optionally substitutedC₁-C₄ aliphatic.
 12. The compound according to claim 5, wherein at leastone occurrence of R⁵ is independently selected from —NHR′, —NH(CH₂)R′,—NH(CH₂)₂R′, —NHCH(CH₃)R′, —NHCH₂C(O)NHR′, —NHCH(CH₃)C(O)NHR′,—NHCH(CH₂CH₃)C(O)NHR′, —NHCH(CH(CH₃)₂)C(O)NHR′, —NHCH(C(CH₃)₃)C(O)NHR′,—NHCH(CH₂CH(CH₃)₂)C(O)NHR′, —NHCH(CH₂OH)C(O)NHR′, —NHCH(CH₂OMe)C(O)NHR′or —NHCH(CH₂CH₂N(Me)₂)C(O)NHR′, wherein R′ is an optionally substitutedphenyl.
 13. The compound according to claim 5, wherein at least oneoccurrence of R⁵ is —NHCH(CH₃)R′, wherein R′ is optionally substitutedphenyl.
 14. The compound according to claim 5, wherein at least oneoccurrence of R⁵ is halogen, CH₃, CF₃, COOH, COOMe or OR′, wherein R′ isC₁-C₄ aliphatic.
 15. The compound according to claim 5, wherein x is 2or 3 and at least one occurrence of R⁵ is F.
 16. The compound accordingto claim 5, wherein R⁵ is selected from —NHR′, —NH(CH₂)R′, —NH(CH₂)₂R′,—NHCH(CH₃)R′, —NHCH₂C(O)NHR′, —NHCH(CH₃)C(O)NHR′, —NHCH(CH₂CH₃)C(O)NHR′,—NHCH(CH(CH₃)₂)C(O)NHR′, —NHCH(C(CH₃)₃)C(O)NHR′,—NHCH(CH₂CH(CH₃)₂)C(O)NHR′, —NHCH(CH₂OH)C(O)NHR′, —NHCH(CH₂OMe)C(O)NHR′or —NHCH(CH₂CH₂N(Me)₂)C(O)NHR′, wherein R′ is an optionally substitutedphenyl.
 17. The compound according to claim 5, wherein R⁵ is selectedfrom —NR′CH(CH₂OH)R′, —NR′CH(CH₂OMe)R′, —NR′CH(CH₂OEt)R′,—NR′CH(CH₂OCF₃)R′, —NR′CH(CH₂CH₂OH)R′, —NR′CH(CH₂CH₂OMe)R′,—NR′CH(CH₂CH₂OEt)R′, —NR′CH(CH₂CH₂OCF₃)R′, —NR′CH(CH₃)C(O)OR′,—NR′CH(CF₃)C(O)OR′, —NR′CH(CH₃)C(O)N(R′)₂, —NR′CH(CF₃)C(O)N(R′)₂,—NR′CH(CH₂CH₃)C(O)N(R′)₂, —NR′CH(CH₂OH)C(O)N(R′)₂,—NR′CH(CH₂OMe)C(O)N(R′)₂, —NR′CH(CH₂OEt)C(O)N(R′)₂ or—NR′CH(CH₂OCF₃)C(O)N(R′)₂, wherein R′ is an optionally substituted C₁-C₄aliphatic.